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Malathion metabolism Xenobiotic biotransformation is the process by which foreign compounds (mostly lipophilic) are metabolized through enzymatic

catalysis to metabolites (mostly hydrophilic) that are eliminated directly or after conjugation with endogenous cofactors via renal or biliary excretion. These metabolic enzymes are divided into two groups, Phase I and Phase II enzymes (Rendic and Di Carlo, 1997). Phase I reactions are mediated primarily by cytochrome P450 family of enzymes, but other enzymes (e.g. flavin monooxygenases, peroxidases, amine oxidases, dehydrogenases, xanthine oxidases) also catalyze oxidation of certain functional groups. In addition to the oxidative reactions there are different types of hydrolytic reactions catalysed by enzymes like carboxylesterases and epoxide hydrolases (Low, 1998). Phase I products are not usually eliminated rapidly, but undergo a subsequent reaction in which an endogenous substrate such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid combines with the existing or newly added or exposed functional group to form a highly polar conjugate to make them more easily excreted by decreasing xenobiotic reabsorption from the renal tubule following glomerular filtration or active secretion and from the gastrointestinal tract following biliary secretion. Biotransformation also decreases the entry of xenobiotics into cells of all organs and makes them more suitable for secretion by active transport mechanisms into the bile and urine. (Low 1998) Most xenobiotics follows, or are partly involved in the following steps of which melathion is not an exception, from its absorption to elimination. Absorption Phased 1(functionalization) Xenobiotic bioactivation or detoxification Oxidation, reduction, or hydrolysis cytochrome P450 (CYP) flavin containing monooxygenases alcohol and aldehyde dehydrogenase amine oxidase Lipophilicity excreted directly metabolism OH X phase 2 conjugation reactions glutathione transferase glucuronyl transferase sulfotranseferase thio transferase acetyltransferase glucosyltransferase excretability X excretion O A

Schematic description of two main phases of xenobiotic metabolism. In general a parent compound is converted into an intermediate metabolite which is then conjugated, but metabolism may involve only these reactions, some metabolites are more toxic than the parent compound (Ahokas and Pelkonen 2007) Bioactivation and biotransformation of melathion, an organophosphate insecticide, in mammals and insects is shown below.

Fig 2 Biotransformation and detoxification of melathion The pathways of melathion bioactivation. DMTP, dimethylthiophosphate, DMDTP, dimethydithiophophate, MMA, melathion monocarboxylic acid. MDA, melathion dicarboxylic acid, Buratti et al 2003. As mentioned earlier, when a xenobiotic intrudes or finds its way into living organism, the chemical can be inactivated or detoxified, can be changed into a more toxic substance (bioactivated), or can be changed into other chemical entities having effects that differ both quantitatively and qualitatively from the parent compound. Melathion metabolism follows the same path. Melathion is metabolized mainly in the human liver with a variety of enzyme as indicated on the figure 1 above. When melathion is absorbed into the human or insect body, its metabolism, follows all the pathways shown above in figure2. The human liver microsomal enzyme cytochrome P450, catalyse the oxidation or bioactivation of melathion to the acetylcholinesterase inhibitor malaoxon, causing accumulation of acetylcholine within synapsis and over stimulation of choligenic receptors at the postsynaptic membrane of the nerve cells, with consequent effects such weakness in muscles, muscle convulsion/twitching, and may cause death especially in insects. This pathway is the principal way for melathion metabolism in insects, which results in accumulation of bioactive malaoxon, hence it becomes an effective insecticide. (Buratti 2003 et al.) The principal route of melathion metabolism in mammals is via de-esterification to the and melathion carboxylic acid followed by further metabolism to dicarboxylic acid, This is a

detoxification reaction which increases the excretability of melathion from a mammals body. In this reaction, in which carboxylesterases function to hydrolyse melathion to its mono acids, carboxylesterases competes with the cytochrome P450 catalysed conversion of melathion to malaoxon. Carboxylesterases also convert malaoxon to melathion monocarboxylic acid, as shown on the diagram. The activation reaction is rapid both insects and mammals, whereas hydrolysis to monoacids is rapid in mammals but very slow in insects as a result malaoxon accumulates in insects but not in mammals, resulting in selective toxicity, hence this can accounts for its effectiveness, as an insecticide and its safety to man Malaoxon is further detoxified by paraoxonase enzyme to nontoxic dimethylthiophosphate, an ethyl ether which can be excreted. Cytochrome P450 itself may contribute to melathion detoxication, catalyzing dimethyldithiophosphate formation. Therefore the bioactivation/detoxication balance may be crucial step in determining differences in melathion induced toxicity (Buratti et al 2003). However since carboxylesterases can be inhibited strongly by isomalathion and other impurities in the pesticide melathion, differences in phenotype/genotypes can be relevant in inter individual responses to toxic effects consequent to melathion exposure. The products of metabolism are conjugated to make them more execretable (hydrophilic), through the kidneys in urine and also through the feaces. The hydrolysis of malaoxon in insects is very slow.

References

Buratti FM, Volpe MT, Meneguz A, and Testai E (2003) In vitro metabolism of melathion by human hepatic carboxylesterase and cytochrome P450 isoforms. Drug Metab Rev35:144 Rendic, S. & Di Carlo, F.J. (1997). Human cytochrome P450 enzymes: A status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab. Rev., Vol. 29, No. 1-2, (413-580). Low, L.K. (1998). Metabolic changes of drugs and related organic compounds, In: Wilson and Gisvold's textbook of organic medicinal and pharmaceutical chemistry, Delgado, J.N. & Remers, W.A., (Ed.), (43122), Lippincott-Raven, ISBN: 0397515839, Philadelphia Fundira fact files unpublished.