Organophosphorus compounds. II. Metabolic considerations

Abstract

Organophosphorus compounds are esters of alcohols with phosphoric acids or anhydrides of phosphoric acids with some other acids. The most important groups are the phosphates, phosphorothionates, phosphorothioates, phosphoroamidates, phosphorochloridate and phosphonates. The metabolism of phosphorothionates and phosphorothioates involves initial activation (oxidative desulphuration) followed by hydrolysis of the active metabolites. Activation is carried out by the action of microsomal oxidases, and degradation is performed by different types of hepatic and plasma esterases.

Full text

Vetermary Research Communications, 11 (1987) 589-597
Gee Abstracts Ltd, Norwich - printed in England 589
ORGANOPHOSPHORUS CO MWOLJNDS. II. METABOLIC CONSIDERATIONS
E. 8. ABDELSALAM
Department of Pathology, Faculty of Veterinary Science, University’ of
Khartoum, P.O. Box 32, Khartoum, Sudan
(Accepted: 29 October 1986)
ABSTRACT
Abdelsalam, E.B. 1987. Organophosphorus compounds. II. Metabolic
considerations. Veterinary Research Communications, 11(6) , 589-597
Organophosphorus compounds are esters of alcohols with phosphoric acids
or anhydrides of phosphoric acids with some other acids. The most important
groups are the phosphates, phosphorothionates, phosphorothioates,
phosphoroamidates, phosphorochloridate and phosphonates. The rnetabolism of
phosphorothionates and phosphorothioates involves initial activation (oxidative
desulphuration) followed by hydrolysis of the active metabolites. Activation is
carried out by the action of microsomal oxidases, and degradation is
performed by different. types of hepatic and plasma e&erases.
INTRODUCTION
Organophosphorus compounds (OP) - are esters of alcohols with a
phosphoric acid (e.g. orthophosphoric, pyrophosphoric, thionophosphoric,
thiophosphoric or phosphonic acid) or anhydrides of a phosphoric acid with
some other acids. There are also amides, fluoro and cyanophosphoric
compounds. Most organophosphorus compounds conform to the general formula
(RO)z P(A)X, where R is a methyl or ethyl group, A’ is sulphur or oxygen,
and X is the leaving group which varies in different compounds.
The molecular formula of an organophosphorus compound contains both the
prototype of the phosphoric acid and the side-chain alcohols, e.g. dichlorvos.
is derived from phosphoric acid
CH30’ ’ jp\
C=CClz HO 01
The chemical name is given by naming the alcohols and then the appropriate
phosphoric acid ending and in this case, dichlorvos is dimethyl Z-dichlorovinyl
phosphate.
According to O’Brien (1960; 1967a), organophosphorus compounds
are classified with respect to the atoms attached to the phosphorus radicle
as follows:
0165-7380/87/$03.50 G 1987 Gee Abstracts Ltd

590
RO 0
‘\ //
R O/p’OX
2
i) phosphate
RO
I\,9
R O/ ‘SX
iii) p ‘;, osphorothiolate
(Both are often called phosphorothioates)
R -Nt/ ‘X
2
v) phosphoroamidate
vii) p
% osphorochloridate
S
“; //
1
R Ldp\ ox
2
II) phosphorothionate
“lo\, /
R O/‘SX
2
IV) phosphorodithiolate
RO
‘\,//O
RO”F
2
vi) phosphorofluoridate
R
I\ ,/O
R 0’ \OX
2...
VIII) phosphonate
where Rl, R2 are side chain alcohols and X is the leaving group.
Among these groups, only the phosphates and phosphonates are direct
cholinesterase inhibitors, while the other groups require biological activation
in order to function as anticholinesterases.
METABOLISM AND- BIOTRANSFORMATIONS
The development of more advanced techniques of radioactivity and gas-
liquid chromatography has considerably facilitated the study of different
metabolic pathways of OP compounds and enabled the detection of very
minute residues in tissues and body fluids. Generally speaking, most OP
compounds are readily absorbed,
Absorption can metabolized and excreted (Murphy, 1980).
take place by all possible routes; however, dermal
absorption is exceptionally efficient in certain OP compounds including
demeton, diazinon and coidrin (Clarke et al., 1981). The urine is the main
pathway of excretion (Abou-Donia, 1979; Akiyama et al., 1980; Mount, 1983)
although many OP compounds or their metabolites were also detected in milk
(Kurtz & Hutchinson, 1982; Cooke & Carson, 1985).
The metabolic biotransformations of OP compounds are
complicated and multistep in nature. highly
Most of these reactions are carried out
by different enzyme systems located in the liver microsomes (Davison, 1955;
O’Brien,
DuBois, 1959, 1960; Murphy & DuBois, 1957 ; Dahrn et al., 1962; Neal &
1965; Johnsen & Dahrn, 1966; Vardanis, 1966). Extra hepatic
metabolism of some OP compounds has also been observed in certain tissues
including the brain, lungs, heart, kidneys and blood plasma (Murphy & DuBois,
1957 ; Anderson, 1971; Machin, 1973).

591
Metabolism of phosphorothionates, phosphorothioates and
phosphoroamidates involves initial oxidation (activation) followed by hyorolysis
of the active metabolites ii)ubois, 1961). ,
phosphorothionate \L
R 0”OX
teal kyl ati on
R 0”OX
2 2 2
phosphate
However, there is evidence that phosphorothionates can be direct hyurolysed
witnout prior oxidation, e.g. the airect hydrolysis of EPN ;Neal & IjuBois,
1965) and parathion (Neal, 1967; Nakatsugawa cx Dahm, 1967) into p-
nitrophenol before the formation of their oxons. The phosphate ancl
phosphonate UP compounds are directly degraoed oy the nydrolytic enzymes
since they do not undergo oxidation.
Activation
Activation, i.e. conversion of OP compounds into direct cholinesterase
inhioitors, is the first step in the metabolism of phosphorothionates,
phosphorothioates and phosphoroamidates. Numerous reactions are involved,
including desulfuration, hyaroxylation, tnioether oxidation and cyclization
(O’Brien, 1967a). Oesulfuration is the rnajor reaction in phosphorothionates
and phosphorothioates. It consists of an oxidative removal of the sulphur
atom and its replacement with oxygen, i.e.
P(Sj
to P(U). This reaction is
catalysed by a pyridine-linked enzyme (requires 02 & NAUPHZ) in the liver
microsomes (iueal et al., 1977; Halpert, Hammond cc Neal, lY80; Liegler,
1984). The initial products are presumably sulphoxides which undergo a
number of rearrangement and decomposition reactions but the final proaucts
are the corresponding oxons.
Example:- desul furatio
(c~H~O)~P(S)O~NO~ 02;NADPH 2 (C2HSO)2P(0)OoN0 2
(parathion) (paraoxon)
The releaseu sulphur could be reouced to HzS by glutathione and the
rapid local regeneration of H2S may De responsible for the hepatotoxicity and
destruction of cytochrome P-45U observed in animals treated with cerLain
phosphorothioates such as parathion (Liegler, lYd4).
Activation of phosphoramidates such
(octamethylpyroptlosphoramidej is carried out by nydroyyylation schradan
and/or
oxidation. Hydroxylation of the alkyl group gives hyUroxy1 alkyd derivatives
but the main toxic action is due to oxidation of tne N-methyl group giving a
phosphoramide oxiae as an active product.

592
Degradation
Degradation occurs primarily by hydrolytic routes. The major reactions
involve the cleavage at the aryloxy-phosphate bond yielding phenols and
dialkyl phosphates (Neal & DuBois, 1965). These reactions are mostly carried
out by a number of enzymes collectively known as non-specific esterases
present in the liver, plasma and some other tissues. However, certain
degradation reactions are also catalysed by the hepatic microsomal enzymes,
e.g. the direct degradation of the phosphorothionates is catalysed by a
NADPH+ dependent microsomal oxidase (Neal, 1967). These oxidases are also
involved in dealkyiation of many UP compounas.
The role of microsomal enzymes
The role of hepatic microsomal enzymes in the metabolism of drugs and
other chemicals has been thoroughly discussed (Conney Lk Burns, 1962;
Conney, 1967). These enzymes are generally involved in the conversion of
foreign substrates into less toxic or more water soluble metabolites by means
of complex reactions including N-dealkylation, N-demethylation, O-
demethylation, deamination, oxidation and ring nydroxylation. The activity of
these enzymes is induced by a large number of unrelated compounds such as
DDT, dieldrin, BHC, phenobarbitone and many other substances (Conney,
1967). The metabolic effect of these enzymes is not limited to
biotransformation of compounds which induce them but affects other
substrates as well. The induction of hepatic microsomal enzymes involves
protein synthesis and could be suppressed by protein starvation, amino acid
antagonizers such as ethionine, B-Z-thienylamine and actinornycin D and
SKF525A. The effect of the induction of hepatic microsomal enzymes on the
toxicity of OP compounds is variable, depenaing on the structure of the
compound and on whether the role of the microsomes is primarily activation
or degradation. In addition, aifferent enzyrne systems ‘are involved (Vardanis,
1966) which accounts for differences in the consequences. For example, the
pretreatment of mice with phenobarbitone increased the ability of the
hepatic microsomes to oxiaise schradan and malathion but not parathion
(Vardanis, 1966). Similar treatment with phenobarbitone or dieldrin, however,
induced both oxidative ana hydrolytic metabolism of dicrotophos, aimethioate
and phospharnidone (Tseng 6( Menzer, 1974). Induction of hepatic microsomal
enzymes increased the toxicity of azinophosmethyl and of dimethoate in mice
(O’Brien, 1967b; Menzer dc Best, 1968; Menzer, 1970), schradan and parathion
in rats (Weiss & Orzel, 1967; OuUois & Kinoshita, 1968) and diazinon in
calves (Aodelsalam, 1484; AbdeIsalam dc Ford, 1986). On the other hand,
pretreatrnent with phenobarbitone, aldrin, dieldrin, DDT, BHC, cyclizine or
chlorcyclizirie reduced the toxicity of several OP compounds including
parathion (Ball et al., 1954; Alary & Broaeur, 1969) malathion, parathion,
paraoxon and LPN (Welch h Coon, 1964; iirodeur, 1967) parathion, paraoxon,
tetraethylpyrophosphate, diisopropylfluorophosphate, O-ethyl, O-P-
nitrophenylphosphorothioate, guthion and tri-O-tolyl phosphate (Triolo & Coon,
19663 and mipafox and aimetlan (O’Brien, 1967b). The effect of microsomal
enzyme inhibitors such as SKF525A was also variable. Generally, SKF525A
inhibits the activation of phosphorothionates, but sometimes it seems to have
the opposite effect (O’Brien, lY61). Pretreatment of mice with SKFSZSA
increased the toxicity of phorate (O’Brien, 1961) malathion, parathion and
EPN (Welch h Coon, 1964) parathion and ethyl guthion (Levine h Murphy,
1977) and reducea the toxicity of dimethoate, scradon, dimefox and mipafox
(O’Brien, 196i) and methyl parathion and guthion (Levine and Murphy, 1977).
SKF525A had no effect on the toxicity of paraoxon, TEPP, chlorthion,
cournaphos, diazinon, dioxatllion and ronnel.

593
The role of e&erases
Esterases are complex enzymes widely distributed in animals, plants and
micro-organisms. They catalyse the hydrolysis of different aromatic and
aliphatic esters, thioesters and amides of various substances including the
organosphosphorus compounus. Aldridge (1953a) distinguished two types of
plasma esterases: A-esterase, which was not inhibited by UP compounds such
as t600 @araozonj and hydrolysed P-nitrophenyl acetate at a higher rate
than P-nitrophenyl butyrate; ancl B-esterase which was inhibited by E600 and
hyurolysed butyrate at the same or a higher rate than the acetate. He also
showed that the enzyme catalysing the hydrolysis of paraoxon was identical
with A-esterase (Aldridge, 19530). The same enzyme was later identified as
arylesterase. Satisfactory classification of esterases was not very easy due to
the existence of multiple forms and to the wide and frequently overlapping
substrate specifities (Junge bc Krisch, 1975). The important groups in relation
to the metabolism of CIP compounds are the carboxylic ester hydrolases
which include the carboxylesterases and arylesterases.
Carboxyiesterases LE.C.3.1.i.l.) comprise an enzyme or a group of
enzymes acting on carboxylic ester bonds of different substances, yielding
alcohols and carboxylic acid anions. Originally they were classed as type lj-
esterases of AIdridge. They were also known as aliesterases, i.e. acting on
simple aliphatic esters, but this name is no longer used because the enzyme
was found to be equally able to hydrolyse aliphatic esters such as methyl
butyrate ano aromatic esters such as P-nitrophenyl acetate (Dixon Cx Webb,
1964; Junge b Krisch, 1975). The physiological function of carboxylesterases
in normal metabolism is not fully known, although Myers et al, (1957)
suggesteu that they might have a role in protein metaoolism due to their
ability to hydrolyse amino acid esters and amides. The ability of some liver
caruoxylesterases to catalyse the formation of dipeptides frorn amino acia
esters has also suggested their possible role in protein synthesis (Krenitsky ik
Fruton, 1966). Carooxylesterases are inhibited by a number of UP compounds,
particularly diethyl P-nitrophenyl phosphate (Aldridge, 19>3aj, tri-O-tolyl
phosphate (Myers tx Mendel, 1953) ano EPN (UuBois et al., 1966). However,
their possible role in metabolic detoxification of UP compounds by hydrolysis
of the carboxylester and carboxy amide linkage of certain UPS such as
malathion ano uimethoate has been investigated (Myers, 1960; Main eY Braid,
196.2; Murphy, 1VbOj.
Carboxylesterase activity coulo be stimulated by the administration of
nepatic microsomal enzyme inducers. This was first observed by Crevier et al
(1954j who found that pretreatment of rats with chlorinatea hydrocarbons
increaseu the activity of plasma aliesterases (carboxylesterases). Further
reports have shown that the administration of phenobarbitone and other
microsomal enzyme inducers increased liver carboxylesterase activity (Read
et al., 1964; Lundquist & Perlmann, 1966; Brodeur, 1967; Schwark &
Ecobichon, lV6b; Junge b Krisch, lY75). The experimental induction of
carboxylesterase activity in rats and/or mice protected them against the
toxicity of certain OP compounds including parathion (Ball et al., 1954; Alary
& Broueur, IYGY) parathion, malathion and EPN (Welch & Coon, lY64; Triolo
Ly( Coon, 1966; Brodeur, 1967).
Arylesterases iE.C.3.l.i.Zj, also described by Aldridye (1953 a,bj as A-
esterases, which are not inhibiteo oy E600 or physostigmine, act on phenolic
esters such as phenyl acetate to yielo phenol and acelic acid. Their
physiological function is not well known. t-lowever, they are reported to oe
involved in tile Lransport to the liver of long chain free fatty acids wnich
arise by hyorolysis of lipoproteins in the serum, heart and lungs (Pilz, iV74).
arylesterases are not only resistant to inhibition by the organopthosphorus
colnpounds, but are also involvea in the hydrolytic degrations of most OP
compounds (Aldriuge, 1953; cj’Brien, lY60; iviurphy, 1YUOj.

594
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