ArticlePDF Available

Alpha-glutathione-s-transferase can be a biomarker for both drug-related toxicity as well as individual susceptibility

January 2016

January 2016
57(2):62-71

Authors:

Gazi University

BACKGROUND: Psychiatric disorders are health concern. The important issue is that the response of treatment of patients is different. Some patients are in remission, some suffer from adverse drug reactions (ADRs). Hepatic function is monitored by liver enzymes. It is important to detect liver injury and its evaluation according to the genetic polymorphisms in early phase of treatment. Alpha-glutathione-s-transferase (alpha-GST) is a sensitive biomarker compared to the liver enzymes. GSTs are phase II conjugation enzymes that detoxify xenobiotic and protect cells from the oxidative stress. GSTM1, GSTT1 and GSTP1 are polymorphic. Null genotypes cause lack of activity. Our aim was to investigate whether alpha-GST might be earlier biomarker than liver enzymes for liver injury and impact of individual susceptibility. METHODS: Blood samples before treatment, 10ï¿½3 days and 3ï¿½1 months of treatments were taken from 132 psychotic disorder patients in treatment. Serum alpha-GST was measured by Enzyme Linked Immunosorbent Assay (ELISA) and GSTs gene polymorphisms were genotyped by Polymerase Chain Reaction. RESULTS: Our data indicated that alpha-GST might be a biomarker for liver injury and GSTs gene polymorphisms had a contribution to the risk of psychotic disorders. CONCLUSIONS: Our results encourage making research on finding more specific biomarker and individual susceptibility with larger sample size. ï¿½ 2015 EDIZIONI MINERVA MEDICA.

Content uploaded by Bensu Karahalil

Content may be subject to copyright.

62 MINERVA PSICHIATRICA June 2016

sleep, obesity, nephrotoxicity and hepatotox-

icity) are observed.2 One of the most impor-

tant ADR is hepatotoxicity. The incidence of

hepatotoxicity is between 0.001% and 0.1%.3

Hepatotoxicity is a major concern for pharma-

ceutical companies since it can lead to drug

withdrawal after marketing, or during phase

II or III clinical trials.4 Thus, it is important

to nd biomarkers to detect hepatotoxicity in

early stage, to investigate the mechanisms of

hepatotoxicity, to identify the factors that in-

Psychiatric disorders are a very serious

personal problem and economic burden.

They are an important public health problem

worldwide.1 Drug therapy is a major approach

in psychiatric disorders medication. There is,

however, the clinical problem that patients ex-

hibit signicant differences in drug response

with same dose and the same drug treatment.

While some patients recovered, some do not

heal moreover, and adverse drug reactions

(ADRs) (such as headache, nausea, dizziness,

ORIGINAL ARTICLE

Alpha-glutathione-s-transferase can be

a biomarker for both drug-related toxicity

as well as individual susceptibility

Melda CİBA 1, Mehmet AK 2 , Bensu KARAHALİL 1 *

1Department of Toxicology, Faculty of Pharmacy, Gazi University, Ankara, Turkey; 2Department of Psychiatry,

Faculty of Medicine, Konya Necmettin Erbakan University, Konya, Turkey

*Corresponding author: Bensu Karahalil, Department of Toxicology, Faculty of Pharmacy, Gazi University, 06330, Ankara, Turkey.

E-mail: bensuka@gmail.com

Anno: 2016

Mese: June

Volume: 57

No: 2

Rivista: Minerva Psichiatrica

Cod Rivista: Minerva Psichiatr

Lavoro: 1893-MPSI

titolo breve: IMPACT OF GENETIC BACKGROUND ON ALPHA-GST

primo autore: CİBA

pagine: 62-71

citazione: Minerva Psichiatr 2016;57:62-71

ABSTRACT

BACKGROUNDː Psychiatric disorders are health concern. The important issue is that the response of treatment of

patients is different. Some patients are in remission, some suffer from adverse drug reactions (ADRs). Hepatic function

is monitored by liver enzymes. It is important to detect liver injury and its evaluation according to the genetic polymor-

phisms in early phase of treatment. Alpha-glutathione-s-transferase (alpha-GST) is a sensitive biomarker compared to

the liver enzymes. GSTs are phase II conjugation enzymes that detoxify xenobiotic and protect cells from the oxidative

stress. GSTM1, GSTT1 and GSTP1 are polymorphic. Null genotypes cause lack of activity. Our aim was to investigate

whether alpha-GST might be earlier biomarker than liver enzymes for liver injury and impact of individual susceptibility.

METHODSː Blood samples before treatment, 10±3 days and 3±1 months of treatments were taken from 132 psychotic

disorder patients in treatment. Serum alpha-GST was measured by Enzyme Linked Immunosorbent Assay (ELISA) and

GSTs gene polymorphisms were genotyped by Polymerase Chain Reaction.

RESULTSː Our data indicated that alpha-GST might be a biomarker for liver injury and GSTs gene polymorphisms had

a contribution to the risk of psychotic disorders.

CONCLUSIONSː Our results encourage making research on nding more specic biomarker and individual susceptibil-

ity with larger sample size.

(Cite this article as: Ciba M, Ak M, Karahalil B. Alpha-glutathione-s-transferase can be a biomarker for both drug-related

toxicity as well as individual susceptibility. Minerva Psichiatr 2016;57:62-71)

Key words: Antipsychotic agents - Psychotic disorders - Glutathione S-transferase alpha - Polymorphism, genetic -

Polymerase chain reaction.

Minerva Psichiatrica 2016 June;57(2):62-71

The online version of this article is located at http://www.minervamedica.it

MINERVA MEDICA

This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies

(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other

means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is

not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or ter ms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,

or other proprietary information of the Publisher.

IMPACT OF GENETIC BACKGROUND ON ALPHA-GST CİBA

Vol. 57 - No. 2 MINERVA PSICHIATRICA 63

it is shown that alpha-GST is earlier biomarker

than liver enzymes, it provides immediately,

without any delay, starting an alternative drug

treatment. The levels of alpha-GST were mea-

sured by ELISA (Enzyme Linked Immunosor-

bent Assay) in patients with psychotic disorder

and treated with antipsychotic drugs, GSTM1

and GSTT1 gene polymorphisms were analyzed

by Multiplex (M) and Restriction Fragment

Length Polymorphism (RFLP) Polymerase

Chain Reaction (PCR). Before and during treat-

ment, the levels of liver enzymes were measured

in hospital and were registered to the question-

naires by physician. Serum alpha-GST and liver

enzyme levels were compared to each other. The

impact of GSTs gene polymorphisms on alpha-

GST was analyzed. Data on the present study

can be helpful 1) to diagnose toxicity at early

stage; 2) to provide immediately switch to an-

other drug; 3) to protect from both the drug itself

and the result of its secondary complications.

Materials and methods

In total, 132 unrelated Turkish patients with

clinically denite schizophrenia were par-

ticipated in this study from Gülhane Military

Medical Academy, Psychiatry Clinics. All pa-

tients were diagnosed according to the criteria

DSM IV (The Diagnostic and Statistical Manu-

al of Mental Disorders). The present study was

approved by ethics committees at Keçiören

Education and Research Hospital. The mean

age of the patients was 21.09±7.40 and all pa-

tients were male. Smokers and nonsmokers

comprised of 35.6% and 64.4%. A percentage

of 35.6% of patients had alcohol consumption,

63.6% did not. Peripheral blood samples were

collected from patients at three different time

points [before treatment (A), 10±3 days (B)

and 3±1 months of treatments (C)] There have

been many studies showing that these time pe-

riods are right time to observe possible liver

toxicity of antipsychotic drugs.9-11 Patients

were informed and they lled consent from.

Patients answered the standardized question-

naires related to their medical history, exposure

and lifestyle factors such as smoking, drug con-

sumption, diseases, in case; such factors might

crease the hepatotoxicity. Hepatic function is

routinely monitored by liver enzymes, which

are released into the circulation, in clinic. If

hepatocellular damage occurs, the increase in

the liver enzymes (upper limit of average 1.5-

2 times higher) gives preliminary idea about

hepatic function. Hepatic functions of patients

treated with antipsychotic drugs are monitored

by the following enzymes: Alanine transami-

nase (ALT), Aspartate transaminase (AST),

gamma glutamyltranspeptidase (GGT), alka-

line phosphatase (ALP), total bilirubin (TB),

direct bilirubin (DB), lactate dehydrogenase

(LDH).5 Alpha-GST commonly exists in hepa-

tocytes but is not routinely used in clinic. GST

is much more specic than liver enzymes since

GST has a large hepatic distribution, high cy-

tosolic concentration and short plasma half-

life. Reactive metabolites, such as toxic in-

termediate toxic metabolites of antipsychotic

drugs, increase the membrane permeability by

destroying the hepatocytes.6 While alpha-GST

elevates in hepatotoxicity, liver enzymes (rou-

tinely used in clinic) are not be able to change.

So far there has been no study on alpha-GST

and drug toxicity; there are only a few studies

on alpha-GST and liver diseases. Therefore,

we aimed to investigate whether alpha-GST

was earlier biomarker than liver enzymes for

liver injury and the impact of individual sus-

ceptibility. Glutathione-S-transferases (GSTs)

are phase II conjugation enzymes that catalyze

the detoxication of xenobiotic and endogen

substances and protect cells from the oxidative

stress.7 They are highly polymorphic and the

activity of GST is low or lack of activity in

null and mutant genotypes.8 Thus, the toxic-

ity cannot be neutralized because of low glu-

tathione conjugation. Hepatotoxicity and its

primer complications are not experienced in

all patients. Thus, the impact of individual

susceptibility on alpha-GST was assessed by

evaluating the association between alpha-GST

activity and GST genotypes.

The results of the present study can be useful

to avoid the drug-induced liver damage by the

simple and rapid determination of the GSTM1,

GSTT1 and GSTP1 genotypes and serum alpha-

GST levels of the patients before therapy. When

MINERVA MEDICA

or other proprietary information of the Publisher.

CİBA IMPACT OF GENETIC BACKGROUND ON ALPHA-GST

64 MINERVA PSICHIATRICA June 2016

GSTM1 and GSTT1 genotypes were scored

only if the PCR signal corresponding to the

CYP1A1 internal control was evident. PCR

products were digested with BsmAI (Fermen-

tas Company, Lithuania for GSTP1 (Ile105V-

al) and visualized on 2% agarose gel. Digested

products for GSTP1 are the Ile/Ile, Ile/Val and

Val/Val genotypes resulted in 176 bp; 176, 93

and 83bp.13, 14

Quantitative detection of serum alpha-GST

levels by Enzyme-linked Immunosorbent As-

say (ELISA)

The serum alpha-GST levels were detected

according to the manufacturer’s instructions

(Alpco, 69-AGTHU-E01).

Statistical analysis

The data were analyzed on SPSS software

version 20 (SPPS 20, IBM Corp. Released

2011, IBM SPSS Statistics for Windows,

and Version 20.0. Armonk, NY: IBM Corp.).

Bonferroni corrections were used for multiple

have a confounding effect. Only these patients

who did not use antipsychotic drug therapy in

last three months before participating to the

present study were selected, as well as all sub-

jects who had not any diseases and drugs which

cause the elevation on liver enzymes.

DNA isolation

DNA was isolated from peripheral blood of

each individual by extracting it with sodium per-

chlorate/chloroform.12 The quality and quantity

of DNA was checked by gel electrophoresis and

spectrophotometry using Nanodrop Analyzer

spectrophotometer. The ratio of absorbance at

260 and 280 nm of DNA was around 1.7-1.9.

GSTM1 and GTST1 gene polymorphisms by

Simultaneous Multiplex PCR and GSTP-

1gene polymorphism by RFLP-PCR

Table I summarizes sequences of primers,

Table II shows the contents of PCR tube and

Table III demonstrates thermal cycling condi-

tions.

Table I.—Primers for all studied gene.

Primers (5’-3’) PCR product size (bp)

GSTM1-F

GSTM1-R

GTT GGG CTC AAA TAT ACG GTG G

GAA CTC CCT GAA AAG CTA AAG C

215

CYP2A1-F

CYP2A1-R

GAA CTG CCA CTT CAG CTG TCT

CAG CTG CAT TTG GAA GTG CTC

312

GSTT1-R

GSTT1-F

CTC ACC GGA TCA TGG CCA GCA

AGG CAG CAG TGG GGG AGG ACC

480

GSTP1-R

GSTP1-F

TGA GGG CAC AAC AAC CCC T

ACC CCA GGG CTC TAG GGA A

176

Table II.—PCR tube for genotyping of all studied genes.

PCR tube GSTM1/T1 GSTP1

dNTP 0.25 mmol L-1 0.3 mmol L-1

Taq polymerase 0.5 U µL-1

MgCl21.5 mmol L-1 2 mmol L-1

Taqbuffer (X10) 1X 1X

DNA Örneği 100ng 100ng

Primer F (GSTM1) 1.5 µmol L-1

Primer R (GSTM1) 1.5 µmol L-1

Primer F (GSTT1) 0.8 µmol L-1

Primer R (GSTT1) 0.8 µmol L-1

Primer F (CYP1A1) 0.8 µmol L-1

Primer R (CYP1A1) 0.8 µmol L-1

Primer F (GSTP1) 1.0 µmol L-1

Primer R (GSTP1) 1.0 µmol L-1

MINERVA MEDICA

or other proprietary information of the Publisher.

IMPACT OF GENETIC BACKGROUND ON ALPHA-GST CİBA

Vol. 57 - No. 2 MINERVA PSICHIATRICA 65

treated with nine different antipsychotic drugs.

We evaluated the activities of alpha-GST and

liver enzymes and genetic polymorphisms in

each drug however our sample size was low

for each drug and power analysis results failed.

Therefore, we made all evaluations in total pa-

tients (consisting in nine drugs).

Patients had 40.2% polypharmacy which

did not contain antipsychotic drugs. Table IV

shows the number of patients in each drug.

Distribution was as follows: 31.8% of patients

were treated with olanzapine, 30.3% with ris-

peridone, 10.6% with haloperidol, 9.8% with

aripiprazole, 5.3% with zuclopentixol and ami-

sulpride, and 3.8% with quetiapine, 2.3% with

triuoperazine and 0.8% with ziprasidone.

Frequency of drug distribution for olanzap-

ine, risperidone, haloperidol in our study was

accordance with prescribed drugs in clinics.

Olanzapine, risperidone and haloperidol were

more commonly used than the others (zuclo-

pentixol, amisulpride, quetiapine, triuopera-

zine and ziprasidone).

Alpha-GST versus ALT and AST

Table V shows the percentage increase in al-

pha-GST, ALT and AST levels between A and

B time points. The levels of alpha-GST, ALT

and AST in patients treated with olanzapine,

risperidone and aripiprazole between A and B

time points were 40.81%, 26.53% and 8.16%

for olanzapine, 37.5%, 28.2%, 15.4% for ris-

peridone and 15.38%, 7.69% and 15.38% for

aripiprazole, respectively.

The percentage increase in alpha-GST lev-

els with olanzapine, risperidone and aripip-

razole were statistically higher than ALT and

AST. It was concluded that alpha-GST might

comparisons. Frequencies of the genotypes,

alleles and genotypes were analyzed by Fish-

er’s exact and χ2 Test. Variables were used as

mean±standard deviation, median (max-min),

percentage and frequency. Mauchly’s spheric-

ity and Box-M tests were used to validate a

repeated measures analysis of variance. Box-

Cox transformation was used for parameters

which did not provide prerequisite data. A P-

value<0.05 was considered signicant.

Smoking can inuence liver function. In our

study, smoking habit does not need to be con-

trolled in statistical analysis, since the average

smoking period of patients was 1≤ year.

Results

Peripheral blood samples in three different

time points [before treatment (A), 10±3 days

(B) and 3±1 months of treatments (C)] were

taken from patients. The levels of serum alpha-

GST were measured by ELISA and other liver

enzymes and liver-bile related enzymes (ALT,

AST, GGT, LDH, DB, TB, ALP, Albumin [Ab])

were measured in hospital and registered by

physician to the questionnaires. Patients were

Table III.—Thermal cycling conditions of all studied genes.

SM-PCR RFLP-PCR

Termal cycling conditions GSTM1-T1 GSTP1

Inıtial denaturation 94° C (2 min) 94°C (5 min)

Denaturation 94° C (20 s) 94° C (30 s)

Annealing 59° C (50 s) 64.4° C (30 s)

Extention 72° C (1.5 min);94° C (20 s);59° C (35s); 72° C (1.2 min) 72° C (30 s)

Final elongation 72° C 10 min 72° C (7 min)

The no. of cycles 30

Table IV.—The distribution of patients according to

drugs used in the study.

Drugs The number of patients

Olanzapine 42

Risperidone 40

Aripiprazole 13

Haloperidol 14

Zuclopentixol 7

Amisulpride 7

Quetiapine 5

Triuoperazine 3

Ziprasidone 1

MINERVA MEDICA

or other proprietary information of the Publisher.

CİBA IMPACT OF GENETIC BACKGROUND ON ALPHA-GST

66 MINERVA PSICHIATRICA June 2016

B time point were statistically higher than at

A time point (P<0.001), not with others (AST,

GGT, TB, DB, LDH and ALP). While alpha-

GST levels in B time point were 5 times higher

than those in A time point, the levels of ALT in

B time point is only two times higher than in A

time point. These signicance were between A

and B time point, not between A and C; B and

C (P>0.05, Table VI). Only ALT levels were

within the upper limit of normal (normal lev-

els: 35-40 IU/L).

Table VII showed the distribution of

GSTM1, GSTT1 and GSTP1 gene polymor-

phisms. GSTM1 positive and null genotype

frequencies were 37.3% and 60.4%. The fre-

quencies of GSTT1 positive and null were

70.9% and 26.9%. The frequencies of GSTP1

for Ile105Ile, Ile105Val and Val105Val were

21.6%, 59% and 16.4%. The observed allele

and genotype frequencies of GSTM1, GSTT1

and GSTP1 for patients with psychotic dis-

orders in Turkish population were within the

range described for the previous studies car-

ried out patients with psychotic disorders.15, 16

be more sensitive than the others (ALT and

AST). No statistically signicant increases

were observed with other drugs (haloperidol,

zuclopentixol, amisulpride, quetiapine, tri-

uoperazine and ziprasidone). No differences

were obtained between A and C, and B-C time

points. The reason for insignicance can be

due to small sample size in C time point.

Alpha-GST versus GGT, LDH, DB, TB, ALP, Ab

There was no difference between the per-

centage increase in alpha-GST and others

(GGT, LDH, DB, TB, ALP, Ab).

Alpha-GST activities

Table VI summarized the levels of alpha-

GST and liver enzymes at three different time

points (A, B and C). Alpha-GST and liver en-

zymes were compared to each other among

three different time points. Only alpha-GST

(2.19±4.74 at A, 11.33±25.47 at B) and ALT

levels (27.58±28.68 at A, 42.64±55.78 at B) at

Table V.—The percentage increase in alpha-GST, ALT and AST levels from A to B time points.*

Antipsycotic drug Parameter The percentage increase per subject

(between A and B time points)

Olanzapine Alpha-GST 40.81

ALT 26.53

AST 8.16

Risperidone Alpha-GST 37.5

ALT 28.20

AST 15.38

Aripiprazole Alfa GST 15.38

ALT 7.69

AST 15.38

P<0.001; *no signicant increases were observed other drugs and in C time period.

Table VI.—The levels of alpha-GST and liver enzymes at 3 different time points in times A, B and C.

A (n)

Mean±SD B (n)

Mean±SD C (n)

Mean±SD P

Alpha-GST (μg/L) 2.19±4.74 a (125) 11.33±25.47 (112) 1.70±5.12 (57) 0.001**

ALT (U/L) 27.58 a ±28.68 (132) 42.64±55.78 (115) 24.07±11.77(56) 0.001**

AST (U/L) 30.79±20.31(131) 32.32±21.57 (114) 23.05±5.70 (54) 0.345

GGT (U/L) 24.57±15.23 (107) 28.38±16.48 (101) 27.65±19.30 (46) 0.432

Total Bilirubin (mg/dL) 0.78±0.62 (112) 0.58±0.40 (100) 0.70±0.41 (17) 0.672

Direct Bilirubin (mg/dL) 0.15±0.09 (105) 0.12±0.09 (98) 0.18±0.22 (17) 0.123

LDH (U/L) 410.05 ab ±191.56 (87) 373.34±141.48 (79) 356.27±81.00 (37) 0.03*

ALP (U/L) 121.41±35.34 (102) 112.33±26.37 (92) 119.01±36.22 (53) 0.095

a: *P<0.05, **P<0.01; b: no meaningful differences.

MINERVA MEDICA

or other proprietary information of the Publisher.

IMPACT OF GENETIC BACKGROUND ON ALPHA-GST CİBA

Vol. 57 - No. 2 MINERVA PSICHIATRICA 67

ly signicant increases were observed for ALT

levels between A and B time points. However,

same signicance was observed with both mu-

tant and wild genotypes (Table IX). No gen-

otype-dependent differences were observed

although the sample size was small.

AST, GGT, LDH, DB, TB, ALP, Ab- GSTs gene

polymorphisms

Same comparisons were made with AST,

GGT, LDH, DB, TB, ALP, Ab. We could not

observe any differences and did not show the

results as a table.

Discussion

Drug-induced hepatotoxicity is generally

unpredictable. The reason of hepatotoxicity

may be from drug or its metabolites and may

lead to either idiosyncratic, toxic metabolite

or immune allergic related hepatotoxicity. Ge-

netic variations in systems of biotransforma-

tion or detoxication may change the toxicity

of some drugs.17 In the present study, our aim

was to demonstrate whether the alpha-GST

was an earlier biomarker than other liver en-

zymes (ALT, AST, GGT, LDH, DB, TB, AP,

Ab). Our results showed that reversible el-

Alpha GST- GSTs gene polymorphisms

Comparisons were made to demonstrate the

impact of GSTs gene polymorphisms on alpha-

GST levels. Comparisons were not done when

sample size was below 10. Our expectations

were to observe the high levels of alpha-GST

in patients with heterozygous or mutant geno-

types due to the lack and low activity. It could

be stated that observed data met our expecta-

tions and statistically signicant increases were

observed between A and B time points accord-

ing to the genotypes. However, the signicance

was not observed only with mutant genotype but

also with wild genotypes. However, increase

in alpha-GST levels from A to B time points

[2.30±4.54 A and 12.36±28.11 B for GSTM1

null)] was higher in patients with mutant and

heterozygous genotypes than in patients with

positive and wild genotypes [2.08±5.28 A and

9.73±21.02 B for GSTM1positive] (Table VIII).

Therefore, alpha-GST did not show genotype-

dependent differences. The reason is that the

sample size was reduced in the sub-compari-

sons (according to genotypes).

ALT- GSTs gene polymorphisms

Same comparisons with ALT were made as

we did for the levels of alpha-GST. Statistical-

Table VII.—The frequencies of GSTM1, GSTT1 and GSTP1 gene polymorphisms.

Null Positive

GSTM1 (%) 60.4 37.3

GSTT1 (%) 26.9 70.9

Ile105Ile Ile105Val Val105Val

GSTP1 (%) 21.6 59.0 16.4

Table VIII.—The associations of alpha-GST levels GSTM1, GSTT1 and GSTP1 gene polymorphisms.

Alpha- GST

ABC

NMean±SD nMean±SD nMean±SD

GSTM1 null 79 2.30±4.54 a 71 12.36±28.11 b 38 1.96±5.76 0.01*

GSTM 1 positive 43 2.08±5.28 a 38 9.73±21.02 b 18 0.41±1 0.04*

GSTT1 null 31 3.19±6.26 a 29 16.54±25.56 b 13 2.68±6.51 0.001**

GSTT1 positive 91 1.89±4.17 a 80 9.60±25.78 b 43 1.09±4.20 0.001**

GSTP1 Ile105Ile 24 2.61±5.87 23 6.65±16.23 16 1.67±5.17 0.578

GSTP1 Ile105Val 77 2.19±4.74 a 68 11.42±20.03 b 29 0.30±1.36 0.001**

GSTP1 Val105Val 20 2.29±378 17 18.43±48.59 10 3.19±8.23 0.999

**P<0.01, *P<0.05; comparisons were not done below N.=10.

MINERVA MEDICA

or other proprietary information of the Publisher.

CİBA IMPACT OF GENETIC BACKGROUND ON ALPHA-GST

68 MINERVA PSICHIATRICA June 2016

tic effects or even suffer from ADRs. There

is wide variability in patient response and

toleration of antipsychotic treatment. Hepa-

totoxicity remains a major challenge in drug

development. Serum ALT activity is a widely

used clinical biomarker of liver damage and

is commonly used to assess the risk of liver

injury during drug development and for drug

approvals by regulatory agencies.18 However,

increases in ALT may also indicate a transient

hepatocellular injury that does not progress

to severe drug induced liver injury (e.g. aspi-

rin, heparin). GSTs are key phase II enzymes

which play critical roles in protection against

products of oxidative stress and electrophilic

products. At least ve related gene families,

mu, alpha, pi, theta and sigma have been iden-

tied and polymorphisms have been reported

for GSTM1, GSTP1 and GSTT1, resulting in

either decreased or altered enzyme activity.

Individual GSTM1 or GSTT1 gene deletion af-

fects body antioxidant biomarkers levels, in-

cluding erythrocyte GST activity, plasma total

antioxidant capacity, and glutathione levels.19

Alpha-GST-diseases

There are conictive results on alpha-GST

levels. Beckett et al. investigated the time

course of hepatocellular damage in patients

admitted after paracetamol overdose by mea-

surement of GST. They hypothesized that the

plasma AST or ALT measurements did not

reect accurately the histological severity of

liver damage, however, plasma GST concen-

trations provided a very sensitive index of

hepatocellular due to quickly and signicant

evations were observed in only alpha-GST

and ALT. No any elevations were seen with

others (GGT, LDH, TB, DB, AP). Therefore,

we focused on these 2 enzymes (alpha-GST

and ALT) and compared them each other to

demonstrate which one was more sensitive

biomarker for possible liver injury. The levels

of alpha-GST in A showed 3-4 times higher

than those in B, whereas only 2 times eleva-

tion was observed with ALT and no any in-

crease was observed with others. Compari-

sons were made to show the impact of GSTs

gene polymorphisms on alpha-GST levels.

Signicant increases were observed between

A and B time points according to the geno-

types. However, the signicance was not ob-

served only with mutant genotype but also

with wild genotypes. Therefore, alpha-GST

did not show genotype-dependent differences.

According to the PubMed database, although

there are reports on single cases with severe

liver cell damage under antipsychotic treat-

ment, no hospital based case-control and

population based study has been to investi-

gate the impact of GSTs gene polymorphisms

on alpha-GST and other liver enzyme levels.

Therefore, we had to discuss the association

between serum alpha-GST levels and diseases

which cause liver injury. Associations were

evaluated between GSTs gene polymorphisms

and psychotic disorders. Psychiatric disorders

and their treatment are inuenced by many

factors, such as genetic and environmental

factors. Antipsychotic drugs induced hepato-

toxicity shows individual susceptibility. Some

patients are in remission after antipsychotic

treatment, whereas others show no therapeu-

Table IX.—The associations of ALT levels in GSTM1, GSTT1 and GSTP1 gene polymorphisms.

Alanine aminotransferase (U/l)

PA BC

nMean±SD NMean±SD nMean±SD

GSTM1 null 81 29.05±34.04a74 47.81±65.15 b 37 25.19±10.94 0.02*

GSTM1 positive 48 25.75±17.46 a 39 32.95±31.70 b 18 19.89±10.30 0.04*

GSTT1 null 35 40.20±47.27 a 29 40.38±32.06 b 14 24.14±13.48 0.04*

GSTT1 positive 94 23.21±16.08 a 84 43.48±62.55 b 41 10.10±22.00 0.001**

GSTP1 Ile105Val 78 28.47±33.44 a 72 41.90±50.64 b 29 21.28±10.33 0.001**

GSTP1 Ile105Ile 28 27.21±21.94 22 37.32±33.81 16 26.63±10.94 0.578

**P<0.01, *P<0.05. Comparisons were not done below N.=10.

MINERVA MEDICA

or other proprietary information of the Publisher.

IMPACT OF GENETIC BACKGROUND ON ALPHA-GST CİBA

Vol. 57 - No. 2 MINERVA PSICHIATRICA 69

tients were within the range described for the

previous studies. Studies on the association

between schizophrenia (SCZ) and GSTs gene

polymorphisms suggested that impairment in

the function of GSTs genes affected the ca-

pacity of the cell to detoxify the oxidized me-

tabolites of catecholamine and increased the

risk of SCZ.27-29 There are studies investigat-

ing the association between severe liver injury

(such as, hepatocellular carcinoma) and GSTs

gene polymorphisms. However, these studies

have yielded contradictory results, with some

studies showing a signicant association,

while others showing no such association. Li

et al. conducted a meta-analysis on the as-

sociations with GTSM1 gene polymorphism

and hepatocellular carcinoma risk. Their data

showed that there was signicant associa-

tion (OR=1.5,% CI=1.25-1.80; P<0.05) in 26

articles with 3769 cases and 5517 controls

from the Chinese population, however, no

signicant association in subgroups of publi-

cation in English (OR [95% CI]=1.20 [0.88-

1.64], P=0.24) and in Indian populations

(OR=1.80,% CI=0.80-4.20, P=0.15). They

concluded that the GSTM1 deletion polymor-

phism might not have a signicant effect on

the susceptibility of hepatocellular carcinoma

overall.30 Our results are concordance with

theirs (subgroups of publication in English

and Indian populations). We also did not ob-

serve a signicant association between GSTs

gene polymorphisms and alpha-GST and oth-

er liver function tests. The reason of differ-

ences might be due to ethnicity. Hashemi et

al. also observed signicant association with

GSTM1 and GSTT1 gene polymorphisms but

not GSTP1 in patients with liver diseases.31

GSTs and XRCC1 gene polymorphisms had

no impact on acute rejection in liver transplant

recipients and hepatitis B-related hepatocellu-

lar carcinoma.32

Conclusions

In conclusion, now it is well known that

ADRs could be reduced by modifying drug

selection or dosing in patients with defect in

their drug metabolizing enzymes because of

quantity release of GST. Assessment of eleva-

tions on GST, which is earlier biomarker than

AST and ALT, provided prompt treatment with

N- acetylcysteine of hepatotoxicity.20 Alpha-

GST does not have clinical relevance as mark-

ers of recent alcohol intake and in cirrhotic pa-

tients and furthermore, does not provide more

information than other liver enzymes. How-

ever, alpha-GST determination may be useful

in selecting a subgroup of alcoholics in whom

routine biochemical markers of liver damage

are within reference ranges.21 In patients with

HCV-related chronic hepatitis, alpha-GST lev-

els may be utilized as reliable markers in mon-

itoring the response to interferon treatment.22

Beckett et al. investigated hepatocellular integ-

rity and compared GST levels with ALT, AST,

gamma-glutamyltranferase in patients with

hyperthyroid and hypothyroid patients before

and after treatment. They concluded that GST

was 10 times more sensitive at detecting dam-

age than liver enzymes. Our results on alpha-

GST are concordance with the previous stud-

ies.20, 22, 23 Alpha-GST is a cytosolic enzyme

of the liver with a short half-life. It may not

only sensitively detect hepatocellular injury,

but may also normalize quickly after cessation

of liver damage. Alpha-GST measurements

improve the monitoring after liver transplan-

tation and response to some medications with

some drugs.23,

Gene polymorphisms-disease

Most studies have been done on the metabo-

lizing gene polymorphism (such as, CYP2D6,

CYP2E1, CYP1A1) to evaluate individual dif-

ferences in response to treatment of patients

with psychotic disorders,25-27 and to demon-

strate the association between psychotic dis-

orders and gene polymorphisms.27-29 No study

has been on the association between alpha-

GST levels and GSTs gene polymorphisms.

Hereby, it was discussed the associations be-

tween gene polymorphisms and the risk of

psychotic disorders. All subjects in our study

consisted of patients with psychotic disorders.

The observed allele and genotype frequencies

of GSTM1, GSTT1 and GSTP1 for our pa-

MINERVA MEDICA

or other proprietary information of the Publisher.

CİBA IMPACT OF GENETIC BACKGROUND ON ALPHA-GST

70 MINERVA PSICHIATRICA June 2016

mellitus risk: a case-control study in a Turkish popula-

tion. Gene 2012;505:121-7.

14. Karahalil B, Orhan G, Ak F. The impact of detoxifying

and repair gene polymorphisms and the levels of serum

ROS in the susceptibility to multiple sclerosis. Clin Neu-

rol Neurosurg 2015;139:288-94.

15. Mohammadynejad P, Saadat I, Ghanizadeh A, Saadat M.

Bipolar disorder and polymorphisms of glutathione S-

transferases M1 (GSTM1) and T1 (GSTT1). Psychiatry

Res 2011;186;144-6.

16. Raffa M, Lakhdar R, Ghachem M, Barhoumi S, Sa-

far MT, Bel Hadj Jrad B, et al. Relationship between

GSTM1 and GSTT1 polymorphisms and schizophre-

nia: a case-control study in a Tunisian population. Gene

2013;512:282-5.

17. Larrey D, Pageaux GP. Genetic predisposition to drug-

induced hepatotoxicity. J Hepatol 1997;26:12-21.

18. Ozer JM, Ratner M, Shaw W, Bailey S, Schomaker S.

The current state of serum biomarkers of hepatotoxicity.

Toxicology 2008;245:194-205.

19. Yuan L, Ma W, Liu J, Meng L, Liu J, Li S, et al. Effects

of GSTM1/GSTT1 gene polymorphism and fruit & veg-

etable consumption on antioxidant biomarkers and cog-

nitive function in the elderly: a community based cross-

sectional study. PLoS One 2014;9:e113588.

20. Beckett GJ, Chapman BJ, Dyson EH, Hayes JD.

Plasma glutathione S-transferase measurements after

paracetamol overdose: evidence for early hepatocellular

damage. Gut 1985a;26:26-31.

21. Loguercio C, de Girolamo V, Cuomo A, Argenzio F, Ian-

notta C, Disalvo D, et al. Determination of plasma alpha-

glutathione-S-transferases in chronic alcohol abusers:

relationship with alcohol intake and liver involvement.

Alcohol 1998;33:366-72.

22. Federico A, Tuccillo C, Crafa E., Loguercio C. The

signicance of alpha-glutathione S-transferase determi-

nation in patients with chronic liver diseases. Minerva

Gastroenterol Dietol 1999;45:181-5.

23. Beckett GJ, Kellett HA, Gow SM, Hussey AJ, Hayes JD,

Toft AD. Raised plasma glutathione S-transferase values

in hyperthyroidism and in hypothyroid patients receiving

thyroxine replacement: evidence for hepatic damage. Br

Med J 1985b;291:427-31.

24. Platz KP, Mueller AR, Haller GW, Müller C, Wenig M,

Neuhaus R, et al. Determination of alpha- and Pi-glutath-

ione-S-transferase will improve monitoring after liver

transplantation. Transplant Proc 1997;29:2827-9.

25. Roh HK, Kim CE, Chung WG, Park CS, Svensson JO,

Bertilsson L. Risperidone metabolism in relation to

CYP2D6*10 allele in Korean schizophrenic patients. Eur

J.Clin Pharmacol 2001;57:671-5.

26. Huo R, Tang K, Wei Z, Shen L, Xiong Y, Wu X, Niu

J, et al. Genetic polymorphisms in CYP2E1: associa-

tion with schizophrenia susceptibility and risperidone

response in the Chinese Han population. PLoS One

2012;7:e34809.

27. Kashani FL, Kordi-Tamandani DM, Sahranavard R,

Hashemi M, Kordi-Tamandani F, Torkamanzehi A. Anal-

ysis of glutathione S-transferase genes polymorphisms

and the risk of schizophrenia in a sample of Iranian popu-

lation. Neuron Glia Biol 2011;7:199-203.

28. Gravina P, Spoletini I, Masini S, Valentini A, Vanni D,

Paladini E, e al. Genetic polymorphisms of glutathione S-

transferases GSTM1, GSTT1, GSTP1 and GSTA1 as risk

factors for schizophrenia. Psychiatry Res 2011;187:454-

29. Matsuzawa D, Hashimoto K, Hashimoto T, Shimizu E,

Watanabe H, Fujita Y, Iyo M. Association study between

the genetic polymorphisms of glutathione-related en-

zymes and schizophrenia in a Japanese population. Am J

Med Genet B Neuropsychiatr Genet 2009;150B:86-94.

genetic variations. Our study suggested that

alpha-GST is an early and sensitive biomark-

er to follow the possible toxicity of the drug

or in monitoring the progression of toxicity

in diseases where treatment is required for a

long time as our study. The routinely mea-

surement of alpha-GST in clinics will ben-

et to prevent unnecessary drug loading and

drug-induced adverse effects. As the above

association studies need to be done with the

large sample size.

References

1. Kessler RC, Aguilar-Gaxiola S, Alonso J, Chatterji S, Lee

S, Ormel J, et al. The global burden of mental disorders:

an update from the WHO World Mental Health (WMH)

surveys. Epidemiol Psichiatr Soc 2009;18:23-33.

2. Ma Q, Lu AY. Pharmacogenetics, pharmacogenom-

ics, and individualized medicine. Pharmacol Rev

2011;63:437-59.

3. Sedky K, Nazir R, Joshi A, Kaur G, Lippmann S. Which

psychotropic medications induce hepatotoxicity? Gen

Hosp Psychiatry 2012;34:53-61.

4. Singhal R, Harrill AH, Menguy-Vacheron F, Jayyosi Z,

Benzerdjeb H, Watkins PB. Benign elevations in serum

aminotransferases and biomarkers of hepatotoxicity in

healthy volunteers treated with cholestyramine. BMC

Pharmacol Toxicol 2014;15:42-7.

5. Food and Drug administration, FDA; [Internet]. Avail-

able from: http://www.fda.gov/Drugs [cited 2015, Mar

13].

6. Helaly GF, Mahmoud MM. Diagnostic value of alpha-

glutathione S-transferase as a sensitive marker of in-

creased risk for hepatocellular damage in hepatitis C vi-

rus (HCV) infection: relation to HCV viraemia. J Egypt

Public Health Assoc 2003;78:209-23.

7. Karahalil B, Bohr VA, Wilson DM 3rd. Impact of DNA

polymorphisms in key DNA base excision repair pro-

teins on cancer risk. Hum Exp Toxicol 2012;31:981-

1005.

8. Karahalil B, Emerce E, Kocabaş NA, Akkaş E. Associa-

tions between GSTM1 and OGG1 Ser326Cys polymor-

phisms and smoking on chromosomal damage and birth

growth in mothers. Mol Biol Rep 2011;38: 2911-18.

9. Stamatiadis L, Saba G, Benadhira R, Rocamora JF,

Aubriot-Delmas B, Glikman J. et al. Hepatic tolerance

of atypical antipsychotic drugs. Encephale 2002;28:542-

51.

10. Marwick KF, Taylor M, Walker SW. Antipsychotics and

abnormal liver function tests: systematic review. Clin

Neuropharmacol 2012;35:244-53.

11. Atasoy N, Erdogan A, Yalug I, Ozturk U, Konuk N, Atik

L, Ustundag Y.A review of liver function tests during

treatment with atypical antipsychotic drugs: a chart re-

view study. Prog Neuropsychopharmacol Biol Psychiatry

2007;31:1255-60.

12. Karahalil B, Kocabaş NA, Ozçelik T. DNA repair gene

polymorphisms and bladder cancer susceptibility in a

Turkish population. Anticancer Res 2006;26:4955-58.

13. Gönül N, Kadioglu E, Kocabaş NA, Ozkaya M, Kara-

kaya AE, Karahalil B. The role of GSTM1, GSTT1,

GSTP1, and OGG1 polymorphisms in type 2 diabetes

MINERVA MEDICA

or other proprietary information of the Publisher.

IMPACT OF GENETIC BACKGROUND ON ALPHA-GST CİBA

Vol. 57 - No. 2 MINERVA PSICHIATRICA 71

morphisms of glutathione S-transferase genes (GSTM1,

GSTP1 and GSTT1) and breast cancer risk in a sample

Iranian population. Biomark Med 2012;6:797-803.

32. Yu MW, Yang SY, Pan IJ, Lin CL, Liu CJ, Liaw YF, et al.

Polymorphisms in XRCC1 and glutathione S-transferase

genes and hepatitis B-related hepatocellular carcinoma. J

Natl Cancer Inst 2003;95:1485-8.

30. Liu HZ, Peng J, Peng CY, Yan M, Zheng F. Glutath-

ione S-transferase M1 null genotype and hepatocellular

carcinoma susceptibility in China and India: evidence

from an updated meta-analysis. Asian Pac J Cancer Prev

2014;15:4851-6.

31. Hashemi M, Eskandari-Nasab E, Fazaeli A, Taheri M,

Rezaei H, Mashhadi M, et al. Association between poly-

Funding.—This study was supported by a grant from the Scientic and Technological Research Council of Turkey (113S508) and

Gazi University Scientic Research (02/2012-38) project

Conicts of interest.—The authors certify that there is no conict of interest with any nancial organization regarding the material

discussed in the manuscript.

Acknowledgements.—The authors would like to give special thanks to Süleyman Akarsu, Mehmet Koçer and all participants. We wish

also thank to Mustafa Agah Tekindal for statistical analysis.

Manuscript accepted: December 9, 2015. - Manuscript received: December 1, 2015.

MINERVA MEDICA

or other proprietary information of the Publisher.

Investigation of Biomarkers in Sub-Acute Hepatorenal Toxicity against Bulk and Zinc Oxide Nanoparticles Exposed Mice

Article

Aug 2022

Zinc oxide nanoparticles have been utilized and produced at a very large scale due to their wide range of applications. Nevertheless, its toxicity is one of the concerns addressed by various researchers. Widely used methods of measuring plasma zinc have poor sensitivity and impaired specificity. Currently, there is no specific biomarker for determination of excess zinc inside our body is explored well. Furthermore, it is vital to know the toxic effects of zinc oxide nanoparticles and their bulk counterparts at early exposure level on human health due to day to day increased use of zinc oxide nanoparticles in various applications. In current study we investigate the kidney and liver as the primary target organs for toxicity and their oxidative stress parameters. Twenty-four male mice were divided into three groups(n=8). Control (group I) served as vehicle control; group II:50mg/kg ZnO (bulk) and group III:ZnO NPs (50mg/kg nano). The mice were sacrificed after 14 days exposure, liver and kidney tissue toxicity biomarkers were performed. Our results demonstrate increased levels of GPx, metallothionein, GST, and decrease level of ceruloplasmin, GSH:GSSG ratio in bulk ZnO administered animals. The acute kidney toxicity was further confirmed by increased levels of their biomarkers i.e. Kim-1 and Clusterin. The levels of serum cytokines and caspase were also analyzed. Hence, this study investigated the comparative effect of early exposure of zinc oxide nanoparticles (nZnO) and its bulk form and we conclude that at 50mg/kg b.wt dose, ZnO NPs is comparatively safe to bulk ZnO.

Are changes in olanzapine-induced liver enzyme levels associated with GSTT1 , GSTM1 , GSTP1 , and OGG1 gene polymorphisms?

Article

Full-text available

Mar 2024

Olanzapine treatment sometimes produces transient liver biochemistry abnormalities, and such drug-induced liver injuries are mainly monitored by measuring blood levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), whereas alpha-glutathione-S-transferase (α-GST) is not routinely measured in clinics, even though it can serve as an earlier and more specific biomarker of liver damage. Susceptibility to drug-induced liver injury can much depend on the gene polymorphisms regulating the activity of DNA detoxification and repair enzymes. The aim of this study was to evaluate which of the three liver enzymes – α-GST, ALT, and AST – is the most sensitive biomarker of olanzapine-induced liver injury and how their blood levels are affected by the GSTT1 , GSTM1 , GSTP1, and OGG1 gene polymorphisms in 30 olanzapine-treated patients. Contrary to our hypothesis, the increase in serum α-GST levels was not significantly greater than that of the transaminases. ALT turned out to be an earlier biomarker of liver injury than the other two enzymes. No significant association was found between gene polymorphisms and liver enzyme levels, save for GSTP1 Ile/Val + Val/Val and ALT, which points to this genotype as a risk factor for drug-induced liver injury. Future studies might help to identify the underlying mechanisms of transient liver enzyme increase associated with this genotype.

Ciprofloxacin affects the activity of glutathione S- transferase in different rat tissues

Article

Jun 2020

Glutathione S-transferases (GST) are multi-functional proteins involved in the detoxification of xenobiotics and responsible for protecting cells against oxidative stress. The present study investigated the inhibition effects of Ciprofloxacin on GST enzymes in the liver, renal, and pulmonary tissues of the rat. Sixty Wistar rats were separated into 4 groups, 15 rats each (I-IV). Distilled water was used for intraperitoneally injection of group I (control), however rats in other three groups (II, III, and IV) were injected with 50mg/kg, 100mg/kg, and 150mg/kg of Ciprofloxacin, respectively. The inhibitory effects of the Ciprofloxacin doses were evaluated after 2, 4 and 6 hours. The activity of GST enzyme was significantly inhibited in response to Ciprofloxacin doses at different periods and tissues (p<0.05). In all animal groups, GST activity in hepatic tissue was inhibited against the control group almost in all the intervals (p<0.05). For renal tissues, GSH enzyme activities were inhibited in the groups (II-IV) from 2 nd until the end of the 4 th hour period, whereas activation was observed in the next periods (p<0.05). Furthermore, in pulmonary tissues, the inhibitory effect on Glutathione enzyme activity was observed during the 4 th h in Ciprofloxacin groups compared to the control, while after 6 hours, the enzyme showed a different response and has a recovered activity. (p<0.05).

Melatonin ameliorates sodium valproate-induced hepatotoxicity in rats

Article

Full-text available

Jan 2020
MOL BIOL REP

Valproic acid (VPA) is a anticonvulsant and mood-stabilizing agent used to treat epilepsy in patients of all ages. However, it can cause hepatotoxicity with increased oxidative stress. Melatonin (MEL) is known as antioxidant and antiinflammatory agent. Therefore, the present study designed to investigate the probable protective role of melatonin against VPA-induced liver toxicity. For that purpose, 28 Wistar rats were randomly selected and divided into four groups, namely the Group C (vehicle), VPA (500 mg/kg/day VPA), MEL + VPA (10 mg/kg/day melatonin + 500 mg/kg/day VPA) and MEL (10 mg/kg/day melatonin). The agents were given by oral gavage for 14 days. Blood and liver tissue samples from all the rats were harvested on the 15th day of experiment. Biochemical analyses were conducted on the blood samples. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), alpha glutathione S-transferases (α-GST), nuclear factor-κB (NF-κB), myeloperoxidase (MPO) and changes in gene expression were examined in the liver tissues. Also, liver histopathological analyses were conducted. VPA administration significantly increased the levels of α-GST, MDA, NF-κB and of IL-1β, TNF-α gene expression in the liver compared to Group C. Moreover, vacuolization, hydropic degeneration, inflammatory cell infiltration, and sinusoidal congestion were commonly detected in the VPA-treated group along with the highest apoptotic index (TUNEL staining) values. Melatonin administration was revealed to exhibit powerful protective properties at cellular, inflammatory and oxidative level activities against VPA-induced liver toxicity. Therefore, melatonin administration may be used as an adjuvant therapy against to VPA-induced liver toxicity.

Glutathione S-transferase omega gene polymorphism as a biomarker for human papilloma virus and cervical cancer in Iranian women

Article

Full-text available

Aug 2018

Objective: Human papillomavirus (HPV) infection is an important sexually transmitted infection worldwide. Persistent infections with different high-risk HPV genotypes may cause cervical intraepithelial neoplasia and cervical cancer. Single nucleotide polymorphisms of glutathione S-transferase omega (GSTO) 1 and 2 play an important role in cancer progression. This study aims to evaluate GSTO gene polymorphism influence on women's susceptibility to low-risk or high-risk HPV infections and also risk of cervical cancer development. Material and methods: We examined 50 patients with cervical cancer, 43 patients who were positive for HPV, and 43 healthy individuals as negative controls. We used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to determine GSTO1 A140D and GSTO2 N142D variants in study participants. Results: We found a significant association between the GSTO1 A140D gene polymorphism and HPV 6, 16, 18, 16/18 infections and cervical cancer in Iranian women. We noted a significant difference for the 140AD/142NN combination genotype between patients in the cervical cancer group and healthy controls. There were no significant differences for the GSTO2 N142D genotype and allele frequencies between the cases (i.e., cervical cancer and HPV-positive) groups and the controls. Conclusion: The 140AD genotype, 140 D allele, and 140 AD/142NN combination genotype seem to confer a protective property in women's susceptibility to HPV 6, 16, 18, 16/18 infections and cervical cancer. However, GSTO2 N142D polymorphism is not associated with HPV infections and cervical cancer. It would appear that GSTO1A140DSNPs likely play a role in the level of susceptibility to HPV-related cervical cancer.

Hepatotoxicity associated with statins

Article

Full-text available

Oct 2017
Arch Ind Hyg Toxicol

Treatment with statins is known all over the world. They are generally considered safe at therapeutic doses. Nevertheless, clinical trials are not enough to assess their scarce adverse effects such as idiosyncratic drug induced liver injury (DILI). Due to some conditions, such as concomitant usage (drug-drug interaction using an identical metabolising enzyme) and genetic polymorphisms, there is an increasing concern about their safety. Hepatotoxicity and rhabdomyolysis have begun to appear in published studies. Most of investigations have focused on both these adverse effects and mechanisms of drug induced toxicity. The present review has attempted to compile almost all of the existing studies on the hepatotoxicity of statins but not rhabdomyolysis. The aim of our study is to provide an overview of the studies on the statin-associated hepatotoxicity and to discuss the published studies. The researchers are of the opinion that the research on this topic is incomplete but extremely necessary.

Benign elevations in serum aminotransferases and biomarkers of hepatotoxicity in healthy volunteers treated with cholestyramine

Article

Full-text available

Aug 2014

Background There are currently no serum biomarkers capable of distinguishing elevations in serum alanine aminotransferase (ALT) that portend serious liver injury potential from benign elevations such as those occurring during cholestyramine treatment. The aim of the research was to test the hypothesis that newly proposed biomarkers of hepatotoxicity would not significantly rise in serum during elevations in serum ALT associated with cholestyramine treatment, which has never been associated with clinically relevant liver injury. Methods In a double-blind placebo-controlled trial, cholestyramine (8g) was administered for 11 days to healthy adult volunteers. Serum from subjects with elevations in alanine aminotransferase (ALT) exceeding three-fold the upper limit of normal (ULN) were utilized for biomarker quantification. Results In 11 of 67 subjects, cholestyramine treatment resulted in ALT elevation by >3x ULN (mean 6.9 fold; range 3–28 fold). In these 11 subjects, there was a 22.4-fold mean increase in serum levels of miR-122 relative to baseline, supporting a liver origin of the serum ALT. Significant elevations were noted in mean levels of necrosis biomarkers sorbitol dehydrogenase (8.1 fold), cytokeratin 18 (2.1 fold) and HMGB1 (1.7 fold). Caspase-cleaved cytokeratin 18, a biomarker of apoptosis was also significantly elevated (1.7 fold). A rise in glutamate dehydrogenase (7.3 fold) may support mitochondrial dysfunction. Conclusion All toxicity biomarkers measured in this study were elevated along with ALT, confirming the liver origin and reflecting both hepatocyte necrosis and apoptosis. Since cholestyramine treatment has no clinical liver safety concerns, we conclude that interpretation of the biomarkers studied may not be straightforward in the context of assessing liver safety of new drugs.

Impact of DNA polymorphisms in key DNA base excision repair proteins on cancer risk

Article

Full-text available

Oct 2012
HUM EXP TOXICOL

Genetic variation in DNA repair genes can modulate DNA repair capacity and may be related to cancer risk. However, study findings have been inconsistent. Inheritance of variant DNA repair genes is believed to influence individual susceptibility to the development of environmental cancer. Reliable knowledge on which the base excision repair (BER) sequence variants are associated with cancer risk would help elucidate the mechanism of cancer. Given that most of the previous studies had inadequate statistical power, we have conducted a systematic review on sequence variants in three important BER proteins. Here, we review published studies on the association between polymorphism in candidate BER genes and cancer risk. We focused on three key BER genes: 8-oxoguanine DNA glycosylase (OGG1), apurinic/apyrimidinic endonuclease (APE1/APEX1) and x-ray repair cross-complementing group 1 (XRCC1). These specific DNA repair genes were selected because of their critical role in maintaining genome integrity and, based on previous studies, suggesting that single-nucleotide polymorphisms (SNPs) in these genes have protective or deleterious effects on cancer risk. A total of 136 articles in the December 13, 2010 MEDLINE database (National Center for Biotechnology Information, http://www.ncbi.nlm.nih.gov/pubmed/) reporting polymorphism in OGG1, XRCC1 or APE1 genes were analyzed. Many of the reported SNPs had diverse association with specific human cancers. For example, there was a positive association between the OGG1 Ser326Cys variant and gastric and lung cancer, while the XRCC1 Arg399Gln variant was associated with reduced cancer risk. Gene-environment interactions have been noted and may be important for colorectal and lung cancer risk and possibly other human cancers.

Antipsychotics and Abnormal Liver Function Tests: Systematic Review

Article

Full-text available

Sep 2012
CLIN NEUROPHARMACOL

Systematic assessment of the prevalence and pattern of liver function test (LFT) abnormalities associated with regular antipsychotics in adult humans and consideration of management of such abnormalities. Systematic search identifying cohort, cross-sectional or case studies/series, reporting LFT abnormalities in patients receiving regular antipsychotics. EMBASE, PsychINFO, and MEDLINE were searched for studies in English from record onset. Abstracts were independently screened for eligibility by 2 researchers. Ineligible studies included those that did not report LFT reference ranges, those that studied fewer than 10 patients on a given antipsychotic, and those studying children. Key variables in group studies were extracted. Case studies/series were examined for patient outcome. Ten group studies and 91 case studies/series were eligible, although quality was poor. All groups receiving regular antipsychotics had a prevalence of LFT abnormalities greater than chance. The median percentage of patients with any abnormal LFT on any antipsychotic was 32%, with a range of 5% to 78%. The median percentage of patients with clinically significant elevations was 4%, with a range of 0% to 15%. Transaminases were most commonly elevated. Abnormalities were generally asymptomatic, arose within 6 weeks, and were either stably persistent or resolved with continued treatment. Case reports suggested that antipsychotics can be associated with severe hepatitis, fatal in a small minority of cases. Chlorpromazine is most commonly associated with acute liver injury. The LFT abnormalities in patients receiving regular antipsychotics are common but generally mild and transient. Very rarely, a severe or fatal hepatic injury can emerge.

Genetic Polymorphisms in CYP2E1: Association with Schizophrenia Susceptibility and Risperidone Response in the Chinese Han Population

Article

Full-text available

May 2012
PLOS ONE

CYP2E1 is a member of the cytochrome P450 superfamily, which is involved in the metabolism and activation of both endobiotics and xenobiotics. The genetic polymorphisms of CYP2E1 gene (Chromosome 10q26.3, Accession Number NC_000010.10) are reported to be related to the development of several mental diseases and to be involved in the clinical efficacy of some psychiatric medications. We investigated the possible association of CYP2E1 polymorphisms with susceptibility to schizophrenia in the Chinese Han Population as well as the relationship with response to risperidone in schizophrenia patients. In a case-control study, we identified 11 polymorphisms in the 5' flanking region of CYP2E1 in 228 schizophrenia patients and 384 healthy controls of Chinese Han origin. From among the cases, we chose 130 patients who had undergone 8 weeks of risperidone monotherapy to examine the relationship between their response to risperidone and CYP2E1 polymorphisms. Clinical efficacy was assessed using the Brief Psychiatric Rating Scale (BPRS). Statistically significant differences in allele or genotype frequencies were found between cases and controls at rs8192766 (genotype p = 0.0048, permutation p = 0.0483) and rs2070673 (allele: p = 0.0018, permutation p = 0.0199, OR = 1.4528 95%CI = 1.1487-1.8374; genotype: p = 0.0020, permutation p = 0.0225). In addition, a GTCAC haplotype containing 5 SNPs (rs3813867, rs2031920, rs2031921, rs3813870 and rs2031922) was observed to be significantly associated with schizophrenia (p = 7.47E-12, permutation p<0.0001). However, no association was found between CYP2E1 polymorphisms/haplotypes and risperidone response. Our results suggest that CYP2E1 may be a potential risk gene for schizophrenia in the Chinese Han population. However, polymorphisms of the CYP2E1 gene may not contribute significantly to individual differences in the therapeutic efficacy of risperidone. Further studies in larger groups are warranted to confirm our results.

Pharmacogenomics and Individualized Medicine

Article

May 2012

The Impact Of Detoxifying And Repair Gene Polymorphisms And The Levels Of Serum Ros In The Susceptibility To Multiple Sclerosis

Article

Oct 2015

Glutathione S-transferase M1 Null Genotype and Hepatocellular Carcinoma Susceptibility in China and India: Evidence from an Updated Meta-analysis

Article

Jun 2014
ASIAN PAC J CANCER P

Background: Glutathione S-transferase M1 (GSTM1) have been reported to be associated with hepatocellular carcinoma. However, the effect of the GSTM1 null genotype was divergent in the literature and we therefore performed the present meta-analysis to explore the relationship in detail. Materials and methods: Reported studies were searched from 1990 to March 1, 2014 in PubMed and Wanfang Med Online. The total odds oatio (OR) and 95% CI were calculated and analyzed by Review Manager 5.1 and STATE 12. Results: Total OR was calculated from 26 articles with 3,769 cases and 5,517 controls and the association proved significant (OR [95%CI]=1.50 [1.25, 1.80], P<0.05) in the Chinese population. However, there was no significant association between hepatocellular carcinoma risk among subjects carrying the GSTM1 null genotype (OR [95%CI]=1.20 [0.88-1.64], P=0.24) in subgroups of publication in English and in Indian populations (OR [95%CI]=1.80 [0.80- 4.20], P=0.15). Conclusions: The GSTM1 deletion polymorphism might not have a significant effect on the susceptibility of hepatocellular carcinoma overall.

Relationship between GSTM1 and GSTT1 polymorphisms and schizophrenia: A case-control study in a Tunisian population

Article

Oct 2012

There is substantial evidence found in the literature that supports the fact that the presence of oxidative stress may play an important role in the pathophysiology of schizophrenia. The glutathione S-transferases (GSTs) forms one of the major detoxifying groups of enzymes responsible for eliminating products of oxidative stress. Interindividual differences observed in the metabolism of xenobiotics have been attributed to the genetic polymorphism of genes coding for enzymes involved in detoxification. Thus, in this study we investigated the association of Glutathione S-transferase Mu-1 (GSTM1) and Glutathione S-transferase theta-1 (GSTT1) gene deletion polymorphisms and schizophrenia in a Tunisian population. A case-control study including 138 schizophrenic patients and 123 healthy controls was enrolled. The GSTM1 and GSTT1 polymorphisms were analyzed by multiplex polymerase chain reaction (PCR). No association was found between the GSTM1 genotype and schizophrenia. Whereas, the prevalence of the GSTT1 active genotype was significantly higher in the schizophrenic patients (57.2%) than in the controls (45.5%) with (OR =0.6, IC 0.37-0.99, p=0.039). Thus, we noted a significant association between schizophrenia and GSTT1 active genotype. Furthermore, the combination of the GSTM1 and GSTT1 null genotypes showed a non-significant trend to an increased risk of schizophrenia. The present finding indicated that GSTT1 seems to be a candidate gene for susceptibility to schizophrenia in at least Tunisian population.

Analysis of glutathione S-transferase genes polymorphisms and the risk of schizophrenia in a sample of Iranian population

Article

Jul 2012
NEURON GLIA BIOL

Glutathione S-transferases (GSTs) are major intracellular antioxidants, which, impaired in their function, are involved in the progress of schizophrenia (SCZ). The aim of this case-control study was to investigate the association between the polymorphism of glutathione S-transferases M1 (GSTM1), T1 (GSTT1), the glutathione S-transferase P1 gene (GSTP1) and SCZ. We isolated genomic DNA from peripheral blood of 93 individuals with SCZ and 99 healthy control subjects' genotypes analyzing them for GSTM1, GSTT1 and GSTP1 using polymerase chain reaction. The analysis of the gene-gene interaction between GSTs indicated that the magnitude of the association was greater for the combined AG/GSTT1 & GSTM1 genotypes (OR = 2.51; 95% CI: 1.13-5.63, P = 0.02). The AG and combined AG + GG genotypes of GSTP1 increased the risk of SCZ (OR = 1.83; 95% CI: 0.94-3.75 and OR = 1.71; 95% CI: 0.92-3.19, respectively). The genotypes of GSTT/NULL, NULL/GSTM and NULL/NULL increased the risk of SCZ (OR = 2.05; 95% CI: 0.9-4.74; OR = 2.0; 95% CI: 1.68-2.31; and OR = 1.8; 95% CI: 0.57-2.46, respectively). The present study supports previous data that suggest that impairment in the function of GSTs genes may increase the risk of SCZ.

Which psychotropic medications induce hepatotoxicity?

Article

Nov 2011

Safe prescribing practices to minimize pharmaceutically induced liver damage or worsening of preexisting conditions require knowledge about medicines with hepatotoxic potential. This paper reviews psychotropic medications and their effects on the liver. A MEDLINE search was performed utilizing the phrase "drug-induced liver injury" with various categories of psychiatric drugs. Only articles written in English were utilized. Hepatotoxicity can be acute or chronic in nature. Medication discontinuation is necessary in acute forms, while close monitoring is required in milder forms of medication-induced chronic liver damage. Nefazodone, pemoline and/or tacrine are the highest offenders. Carbamazepine and valproate products (e.g., divalproex) can lead to this adverse event and should be avoided in patients with liver disease, persons with alcohol misuse or those consuming high doses of acetaminophen. Knowing the risk levels associated with various medicines is important; prescribing multiple drugs with hepatotoxic effects should be avoided. One should educate patients about early warning signs of liver injury. Always provide clinical and laboratory monitoring before and during the use of hepatotoxic drugs. Clinical features and laboratory results govern medication prescribing with ongoing risk-to-benefit ratio assessment during pharmacotherapy.

Alpha-glutathione-s-transferase can be a biomarker for both drug-related toxicity as well as individual susceptibility

Abstract

Recommended publications

Interactive effects of smoking and glutathione S-transferase polymorphisms on the development of non...

Hypomagnesemia in diabetes patients: comparison of serum and intracellular measurement of responses...

Oxidative stress index in chronic exposure to volatile organic compounds and their relation with gen...

Evaluation of glutathione S-transferase P1 (GSTP1) Ile105Val polymorphism and susceptibility to type...