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LEAD INDUCED EFFECTS ON RENAL ALKALINE PHOSPHATASE WITH ROLE OF ZINC IN ALBINO RATS

Authors:
Naheed Khan at Dow University of Health Sciences
Naheed Khan
Imtiaz Ali Waggan at Dow University of Health Sciences
Imtiaz Ali Waggan
Farrukh Mustafa
Farrukh Mustafa
Farrukh Mustafa
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Khalida Perveen at DOW INTERNATIONAL MEDICAL COLLEGE KARACHI PAKISTAN
Khalida Perveen
  • DOW INTERNATIONAL MEDICAL COLLEGE KARACHI PAKISTAN
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Kidneys are adversely affected by a wide variety of therapeutic agents and chemicals including the environmental pollutants such as Lead. The nephrotoxic effects of lead have been widely studied. The proximal tubular cells are especially vulnerable to lead induced damage to membrane structure and function, characterized by enzymuria and inhibition of certain renal enzymes. Alkaline phosphatase activity is also known to be suppressed which has been evaluated in the present study by enzyme histochemistry. Moreover Zinc, an essential micronutrient has been used to minimize the effects of lead.
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Pakistan Journal of Pharmacology
Vol.28, No.2, July 2011, pp.39-44
LEAD INDUCED EFFECTS ON RENAL ALKALINE
PHOSPHATASE WITH ROLE OF ZINC IN ALBINO RATS
NAHEED KHAN, IMTIAZ WAGGAN,
FARRUKH MUSTAFA AND KHALIDA PERVEEN
Dow Medical College, DUHS, Karachi, Pakistan
ABSTRACT:
Kidneys are adversely affected by a wide variety of therapeutic agents and chemicals
including the environmental pollutants such as Lead. The nephrotoxic effects of lead
have been widely studied. The proximal tubular cells are especially vulnerable to lead
induced damage to membrane structure and function, characterized by enzymuria and
inhibition of certain renal enzymes. Alkaline phosphatase activity is also known to be
suppressed which has been evaluated in the present study by enzyme histochemistry.
Moreover Zinc, an essential micronutrient has been used to minimize the effects of lead.
Keywords: Lead, nephrotoxicity, alkaline phosphatase, zinc, proximal tubules.
INTRODUCTION
The increasing use of therapeutic agents
and chemicals for the last few decades has
considerably increased the possibility of
damage to the kidneys (WHO, 1991).
Nephrotoxic effects of analgesics, antibiotics,
anticancer agents, various household,
industrial and environmental chemicals have
been investigated.
Lead environmental pollution is a major
concern for public health (Oliveira et al.,
2009). Several sources of lead poisoning have
been identified in humans.The most common
are the leaded gasoline, batteries, paints,
ceramics, soldering, and building materials
(ATSDR, 1999),improperly glazed containers
(Klaasen, 2001), gunshot wounds with
retained lead pellets or particles, and a variety
of folk remedies and cosmetics( Meyer et al.,
2008; Woolf et al., 2007).
Besides having detrimental effect on
other organ systems it is also capable of
inducing nephrotoxicity (WHO, 1991) as
kidneys form major route of its excretion
(Noorafshan, 1998).Autopsy studies of lead
exposed humans showed that among soft
tissues, liver is the largest repository followed
by kidney (Sharma et al., 2010).
It is suggested that the mechanism
involved in lead induced toxicity is the metal-
induced reactive oxygen species (Ercal et al.,
2001) which are the initiators of peroxidative
damage to the membranes (Adegbesan and
Adenuga 2007; Sandhir et al., 1994) and cause
impaired membrane function, impaired
structural integrity and inactivation of a
number of membrane bound enzymes (Sidhu
et al., 2004). Lead-induced impairment of
proximal tubular function manifests as
enzymuria (ATSDR, 1999) and inhibition in
the activities of certain renal enzymes which
were also observed in lead administered rats.
The effects of lead were also studied on
isolated brush-border enzymes such as alkaline
phosphatase, that showed a decline upon its
administration (Sivaprasad et al., 2004). A
study by Flora et al (1983) showed that the
oral administration of lead acetate significantly
enhanced the urinary excretion and a
corresponding decrease in renal activities of
Alkaline Phosphatase. Alkaline phosphatase
helps in ionic movement across the cell
membrane and is also associated with
*Corres
p
ondence to: e-mail: drnkhan
@y
ahoo.com
Lead induced effects on renal alkaline phosphatase
40
secretory and absorption processes of the cell
(Bansal and Roy, 1997).
Adequate supply of essential
micronutrients in the diet is known to
minimize the effects of lead. Amongst them
zinc seems to have the maximal effects in
lowering the ill effects of lead (D’Souza et al.,
2003). Dose dependent effects of zinc
supplementation as a chelator in lead treated
rats was reported (Flora et al., 1994).
Zinc supplementation could significantly
compete for and effectively reduce the
availability of binding sites for lead uptake
(Batra et al., 1998). Zinc is an essential
mineral found in almost every cell (Office of
Dietary Supplement – National Institute of
Health, 2002), and plays a biochemical role by
stabilizing membrane structure, thus reducing
per oxidative damage to cell.
The pre-treatment with an essential metal
could prevent the appearance of signs of toxic
metal induced tissue injury (Afonne et al.,
2002) in experimental animals. A study of zinc
deficient patients receiving zinc
supplementation showed increases in alkaline
phosphatase activity that paralleled the degree
of zinc repletion. Important zinc containing
metalloenzymes in humans include alkaline
phosphatase (Milne, 2001).
MATERIALS AND METHODS
The study was carried out on a total of 36
active, young adult Albino rats in the
Department of Anatomy, Basic Medical
Sciences Institute (BMSI), Jinnah Post-
graduate Medical Centre (JPMC), Karachi
At the onset of experimental study, the
animals were divided into three groups
comprising 12 rats each; on the bases of drugs
they received. The drugs were injected
intraperitoneally to ensure uniform absorption.
• Group-A rats served as control, received
injection normal saline 1 ml intra-
peritoneally daily for 6 weeks.
• Group-B rats received Injection Lead
Acetate (Merck, Germany) at a dose of 8
mg/kg body weight intra-peritoneally
daily for 6 weeks.
• Group-C rats received Injection Zinc
Chloride (Merck, Germany) at a dose of
0.21mg/kg body weight intra-peritoneally
two hours before administration of Lead
Acetate at a dose of 8 mg/kg body weight
intra-peritoneally daily for 6 weeks
The animals were sacrificed under ether
anesthesia at the end of experimental period.
The kidneys were obtained and were fixed in
10% formalin for 24 hours, after which
processing, sectioning and staining with
Gomori’s Calcium phosphatase methods were
done. The method was applied for the
histochemical study of enzyme Alkaline
Phosphatase.
OBSERVATIONS AND RESULTS
The present study was designed to
observe the lead induced nephrotoxicity with
role of zinc in albino rats. The histochemical
observations of renal Alkaline phosphatase
were based on the study of sections, stained
with Gomori’s Calcium Phosphate method.
The Gomori’s Calcium Phosphate stained
sections of group A rats showed the sites of
enzyme activity of alkaline phosphatase in the
renal proximal tubules in the form of brownish
black deposits. The deposits were seen
regularly and evenly arranged within the
tubules (Fig. 1).
The Gomori’s Calcium Phosphate stained
sections of group B rats for alkaline
phosphatase showed decreased enzyme
activity in tubules. The brownish black
deposits were decreased as few clumps,
irregularly distributed in renal tubules (Fig. 2).
The Gomori’s Calcium Phosphate stained
sections of group C rats for alkaline
phosphatase showed an increase activity of
enzyme in the tubules, which is comparable to
Khan et al. 41
control. The blackish brown deposits were
seen in the tubules quite regularly arranged
(Fig. 3).
DISCUSSION
It was thought worthwhile to carry out a
study using experimental induction of
nephrotoxicity in albino rats by administration
of lead. Moreover attempts have been made to
study the protective effects of zinc on lead
induced nephrotoxicity.
The histochemical study was done to
observe the effects of lead on activity of
enzyme alkaline phosphatase. The study of
Gomori’s Calcium Phosphatase stained
Fig. 1: Gomori’s Calcium Phosphate stained, 5 µm thick longitudinal section of kidney fro
m
group-A (control) rat showing regularly arranged brownish black deposits of alkaline
phosphatase (ALP) within proximal tubules. Photomicrograph × 1000.
Fig. 2: Gomori’s Calcium Phosphate stained, 5 µm thick, longitudinal section of kidney fro
m
group-B (lead treated) rat showing very few brownish black deposits of alkaline phosphatase
(ALP) irregularly distributed in a few tubules. Photomicrograph × 1000.
Lead induced effects on renal alkaline phosphatase
42
sections of group-B showed a decreased
amount of brownish black deposits in the
proximal tubules and hence a decrease activity
of enzyme alkaline phosphatase as compared
to corresponding controls. This could be
correlated with the study of Flora et al. (1983)
according to which the oral administration of
lead acetate enhanced the urinary excretion
and decrease the renal activities of alkaline
phosphatase. It is also in agreement with the
study of Wapnir et al. (1979) who observed
that administration of lead acetate
intraperitoneally for six weeks to rats
decreased the alkaline phosphatase activity in
kidney homogenates.A marked inhibition of
alkaline phosphatase in kidneys is also
observed in other species such as
Heteropneustes fossillis (Sastry and Agrawal,
1979).
These histochemical findings led us to
conclude that such changes in the activity of
phosphatases could be an adaptation to the
metabolic, structural, and functional alterations
in the organelles of the renal cells due to lead
intoxication (Sivaprasad et al., 2004).
The study of Gomori’s Calcium
Phosphate stained sections in group-C
revealed a greater number of deposits as
compared to group-B, thus showing an
increase in alkaline phosphatase activity. This
could be attributed to the fact that alkaline
phosphatase is a zinc-dependent enzyme and
zinc supplementation showed an increase in
alkaline phosphatase activity (Milne, 2001).
CONCLUSION
It is concluded from this study that higher
lead levels reduces the activities of renal
alkaline phosphatase in experimental rats, and
a pretreatment with zinc improves activity of
renal alkaline phosphatase.
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... Highest concentrations are found in the liver and mineralizing bone, but the enzyme is also present in the intestines, placenta, kidneys, and leukocytes (McComb et al. 1979;Weiss et al., 1989;Iba et al. 2004;Mota et al., 2008). Alkaline phosphatase helps in ionic movement across the cell membrane and is also associated with secretory and absorption processes of the cell ( Bansal and Roy, 1997;Khan et al., 2011). ALPase has role in bone mineralization (Van Hoof and De Broe, 1994;Hui and Tenenbaum, 1998;Mota et al., 2008). ...
PhD dissertation "Histological, Histochemical and Ultrastructural Alterations in Male Albino Rats Treated with Therapeutic Doses of Atorvastatin (Lipitor) and Rosuvastatin (Crestor) Drugs"
Thesis
Full-text available
  • Apr 2013
Summary Statins, such as atorvastatin (ATOR) and rosuvastatin (ROSU) are used as cholesterol-lowering drugs. Because statins widely used, commercially available and increasingly used day by day, with few studies and limited data existed on atorvastatin or rosuvastatin-induced histological, histochemical and ultrastructural changes, the present study was conducted to investigate the potential toxicity of the human equivalent therapeutic doses of ATOR and ROSU in Wistar albino rats. The study was conducted using apparently healthy adult male Wistar albino rats (Rattus norvegicus) obtained from the Laboratory Animal Center (College of Pharmacy, King Saud University, Saudi Arabia). The rats were nearly of the same age (8-10 weeks old) and weighing (220-250 g). All animals were kept in the laboratory conditions for a period of 7 days for acclimatization. Animals were maintained under standard management conditions (light, temperature and humidity) and were fed with commercial rat pellets and drinking water ad libitum. All experiments were conducted in accordance with the guidelines approved by Local Animal Care and Use Committee of King Saud University. A total of 120 adult Wistar male albino rats, were divided randomly into 6 groups of 20 animals each. All doses of treated groups were human equivalent therapeutic doses. Both drugs (ATOR and ROSU) were dissolved in 0.25% sodium carboxymethyle cellulose (CMC). ATOR-treated rats (5mg/kg/day), ATOR-treated rats (2.5mg/kg/day), ROSU-treated rats (2.5mg/kg/day), ROSU-treated rats (1.25mg/kg/day), (vehicle control) was intubated with (1mg/kg/day) (CMC 0.25%) and control rats was treated with (5mg/kg/day) physiological saline. All treatments were administered orally (gavage) for 90 consecutive days. At the end of the experimental period, blood samples were collected from 10 animals from each group. Relevant blood Summary v biochemical parameters (Alkaline phosphatase (ALP), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), creatinine, urea, uric acid, total cholesterol and total protein) were determined. Then animals were sacrificed and tissue samples from liver, kidney, heart, testes, brain and lung were processed for sectioning and examination by light and transmission electron microscope. The results of this study could be summarized as follows: First: Blood chemical alterations: Administration of statins (ATOR) or (ROSU) to all treated groups caused significant increases (P<0.05) in the levels of aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP), creatinine (Cr), urea (Ur), uric acid levels compared with those of the control group after 90 days of exposure to statins. This treatment also induced significant decreases in the levels of cholesterol and total protein. The significant differences were clearly observed in high dose treated-groups [(ATOR 5 mg/kg) and (ROSU 2.5 mg/kg)] more than low dose treated-groups [(ATOR 2.5 mg/kg) and (ROSU 1.25 mg/kg)]. In (CMC, vehicle control) the results showed non-significant differences compared with those of the control group. Second: Gross examination: In terms of the anatomical appearance of organs of control animals during 90- day study period, all therapeutic doses of atorvastatin and rosuvastatin had no effect on gross pathological changes in all investigated organs of all members of treated groups. Third: Histological alterations All statin-treated groups [(ATOR 5 mg/kg), (ATOR 2.5 mg/kg), (ROSU 2.5 mg/kg) and (ROSU 1.25 mg/kg)] showed histological alterations in kidney, liver, heart, lung, brain and testes, especially at the high doses (ATOR 5 mg/kg) and (ROSU 2.5 mg/kg). Renal alterations include the degeneration of the tissues up to the necrotic Summary vi patterns, as well as dilatation of blood capillaries and spacing between the renal tubules due to accumulation of fluid (edema). However, the cortex of kidney showed more damage especially in proximal convoluted tubules (PCT) than the medulla. The liver showed some necrotic and hemorrhagic foci especially in (ATOR 5 mg/kg) and (ROSU 2.5 mg/kg). Hemorrhages and dilatation of the portal space and blood sinusoids of the liver were observed. ROSU had greater effects on the hepatic tissue than ATOR. The heart showed some sort of hemorrhages and wavy appearance of myofibers, as well as the sarcoplasm of some fibers was characterized by granular appearance. The lung tissue showed an increase in the thickness of alveolar walls associated with dilation or collapsing of some pulmonary alveoli. While the testicular tissue showed degenerative changes in some seminiferous tubules leading to partial arrest of spermatogenesis, as well as some necrotic cells and spermatid giant cells were shown in some seminiferous tubules of high dose groups. Moreover, The brain of statins-treated rats showed little changes characterized by slight dilatation of blood capillaries with little edema around the neurons in cerebral cortex. No histological changes were observed in (CMC, vehicle control). Fourth: Histochemical alterations Exposure to statins (ATOR) or (ROSU) caused alterations in content of chemical substances of different rat tissues. All treated groups, especially high doses (ATOR 5 mg/kg) and (ROSU 2.5 mg/kg) manifested less content of proteins in the renal and hepatic tissues compared with control group. Liver tissues in (ATOR 5 mg/kg) and (ROSU 2.5 mg/kg) showed reduction in glycogen content, as well as accumulation of glycogen in subsarcolemma of heart tissue of treated rats. Liver tissue in (ATOR 5 mg/kg) and (ROSU 2.5 mg/kg) showed reduction of neutral lipid droplets compared with control group. The kidney tubules in all treated groups showed an obvious Summary vii increased activity of alkaline phosphatase (ALPase). The liver tissue and kidney tubules in all treated groups showed clear increased activity of glucose-6- phosphatase (G6Pase). In comparison with the liver of control group, apoptotic cells were observed in some hepatocytes of ATOR and ROSU-treated groups. Cytoplasmic inclusions with eosinophilia were observed as hyaline droplets in the cytoplasm of some proximal convoluted tubule (PCT) cells of ATOR and ROSU-treated rats. No histochemical changes were observed in (CMC, vehicle control). Fifth: Ultrastructural alterations The epithelial cells lining the PCT of most statin-treated groups, especially in (ATOR 5 mg/kg) and (ROSU 2.5 mg/kg) showed ultrastructural changes such as cytoplasmic vacuolization, swollen mitochondria with clear destroyed cristae beside presence of large dense bodies inside some of swollen mitochondria. The glomeruli showed damaged endothelial cells of blood capillary and dilation of some glomerular blood capillaries. These changes were clear in most treated groups except G4 in which their kidneys were almost normal. The ultrastructure of hepatocytes of treated groups showed accumulation of lipid droplets and glycogen in cytoplasm of affected hepatocytes. Most hepatocytes nuclei showed irregular shape, swelling of mitochondria and destruction of their cristae. The cardiac muscle of (ATOR 5 mg/kg) and (ROSU 2.5 mg/kg), showed ultrastructural changes in their muscle fibers with clear rupture of some muscle fibers and separation of the fibers from each other together with mitochondria swelling and cristae destruction. Discontinuous of elongation of cardiac muscle fiber was observed which might be due to occurrence of partial decomposition in muscle fibers of some animals. Ultrastructural of cardiac muscle fiber exhibited almost normal structure Summary viii without any changes in muscle fibers and mitochondria in low dose (ATOR 2.5 mg/kg) and (ROSU 1.25 mg/kg). The ultrastructure of skeletal muscle of (ATOR 5 mg/kg) and (ROSU 2.5 mg/kg), showed ruptured muscle fibers and spacing from each other, also showing discontinuous of elongation of muscle fiber and swelling of the mitochondria and destruction of their cristae. 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Amelioration of lead-induced hepatotoxicity by Allium sativum extracts in Swiss albino mice
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  • MUTAT RES-FUND MOL M
Lead poisoning is an important environmental disease that can have life-long adverse health effects. Most susceptible are children, and most commonly exposed are those who are poor and live in developing countries. Studies of children's blood-lead levels (BLLs) are showing cognitive impairment at increasingly lower BLLs. Lead is dangerous at all levels in children. The sources of lead exposure vary among and within countries depending on past and current uses. Sources of lead may be from historic contamination, recycling old lead products, or from manufacturing new products. In all countries that have banned leaded gasoline, average population BLLs have declined rapidly. In many developing countries where leaded gasoline is no longer used, many children and workers are exposed to fugitive emissions and mining wastes. Unexpected lead threats, such as improper disposal of electronics and children's toys contaminated with lead, continue to emerge. The only medical treatment available is chelation, which can save lives of persons with very high BLLs. However, chelating drugs are not always available in developing countries and have limited value in reducing the sequelae of chronic low dose lead exposure. Therefore, the best approach is to prevent exposure to lead. Because a key strategy for preventing lead poisoning is to identify and control or eliminate lead sources, this article highlights several major sources of lead poisoning worldwide. In addition, we recommend three primary prevention strategies for lead poisoning: identify sources, eliminate or control sources, and monitor environmental exposures and hazards.
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Protective role of zinc in nickel induced hepatotoxicity in rats
Article
  • Nov 2004
  • CHEM-BIOL INTERACT
This study was planned to determine the protective role of zinc, if any, in attenuating the toxicity induced by nickel sulfate in rat liver. Female Sprague Dawley (SD) rats received either nickel alone in the dose of 800 mg/l in drinking water, zinc alone in the dose of 227 mg/l in drinking water, and nickel plus zinc or drinking water alone for a total duration of eight weeks. The effects of different treatments were studied on various parameters in rat liver which include antioxidant enzymes, levels of nickel and zinc and histoarchitecture at the light microscopic level. Further, the activities of hepatic marker enzymes AST and ALT were also studied in rat serum. Nickel treatment to the normal control animals, resulted in a significant increase in lipid peroxidation and enzyme activities of catalase and glutathione-S-transferase. On the contrary, nickel treatment to normal rats caused a significant inhibition in the levels of reduced glutathione. Superoxide dismutase activity was found to be decreased which however was not significant. Interestingly, when Zn was supplemented to nickel treated rats, the activities of catalase, and glutathione-S-transferase and the levels of GSH and lipid peroxidation came back to within normal limits. Activities of serum AST and ALT were increased significantly following nickel treatment to normal rats. Simultaneous zinc administration to nickel treated rats tended to restore the altered levels of AST and ALT. Normal control and zinc treated animals revealed normal histology of liver. On the other hand, nickel treated animals showed alterations in normal hepatic histoarchitecture which comprise of vacuolization of the hepatocytes and dilatation of sinusoids as well as increase in the number of bi-nucleated cells. Administration of zinc to nickel treated rats resulted in marked improvement in the structure of hepatocytes, thus emphasizing the protective potential of zinc in restoring the altered hepatic histoarchitecture. The nickel administration to normal rats indicated increased concentrations of nickel and decreased concentrations of zinc. However, zinc effectively brought the altered levels of nickel and zinc to within normal range. The study concludes that zinc has the potential in alleviating the toxic effects of nickel in rat liver because of its property to induce metallothionein (S-rich protein) as a free radical scavenger, or its indirect action in reducing the levels of oxygen reactive species.
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Effects of lead nitrate on the activities of a few enzymes in the kidney and ovary Heteropneustes fossillis
Article
  • Jun 1979
The effect of LC(50) and a sublethal concentration of lead nitrate on the activities of alkaline phosphatase, acid phosphatase, glucose-6-phosphatase, lipase and urease in the kidneys and ovaries of a teleost fish, Channa punctatus has been examined after 96 hr and 30 days respectively. The results show that all the five enzymes in the two tissues are inhibited significantly at both the experimental stages. However, the inhibition produced after 30 days by the sublethal concentration ish higher indicating the cumulative action of lead. Further, the inhibition of enzymes is, more marked in kidney than in the ovary.
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