Malathion Bioactivation in the Human Liver: The Contribution of Different Cytochrome P450 Isoforms

Buratti, Franca M.; D'Aniello, Alessandra; Volpe, Maria Teresa; Meneguz, Annarita; Testai, Emanuela

doi:10.1124/dmd.104.001693

Cited by 105 publications

(71 citation statements)

References 36 publications

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“…In humans, the production of malaoxon from malathion has been shown due to an enzyme in the liver microsome. 13) However, monooxygenase activity and malaoxon residue have not been detected in wheat kernels containing malathion residue. 16,17) Our results support the previous reports showing that monooxygenase does not contribute to the elimination of malathion residue in wheat kernels.…”

Section: Discussionmentioning

confidence: 99%

“…thiomalate, malathion monocarboxylic acid, and desmethyl malathion were shown to be produced by monooxygenase, 2,13) organophosphorus hydrolase, 7) carboxylesterase, 6,8,10,12) and methyltransferase, 11) respectively. Mostafa et al estimated that the degradation of malathion sprayed on cotton and broad beans in field experiments was mainly caused by the carboxylesterases in the crops, judging from the formation of malathion monocarboxylic acid.…”

Section: Malathion Residue In Wheat Kernels Is Degraded By Thion Orgamentioning

confidence: 99%

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Malathion Residue in Wheat Kernels is Degraded by Thion Organophosphorus Pesticide-Specific Carboxylesterase

Yoshii

Tonogai²,

Ueno

et al. 2006

JOURNAL OF HEALTH SCIENCE

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We earlier reported that malathion residue in wheat kernels is enzymatically eliminated by adding water to swell the sample as pretreatment in the official method set forth in the Food Sanitation Law of Japan. We examined the activities of monooxygenase, organophosphorus hydrolase, methyltransferase, and carboxylesterase as possible malathion-degradable enzymes in wheat kernels. GC/MS analysis resulted in no activity of monooxygenase in wheat kernels, because malaoxon was not produced in the reaction mixture of the homogenate incubated with malathion for 4 hr. When five organophosphorus pesticides that have a thioether group (P-S-C) were reacted with the wheat kernel homogenate, no formation of thiol groups was detected with the 5,5′-Dithiobis(2-nitro-benzoic acid) (DTNB) reagent, indicating that there was no activity of organophosphorus hydrolase in the kernels. Pesticides that do not have a carboxylester group but do have a dimethyl thio-or dimethyl dithio-phosphate group were not decomposed by the homogenate, suggesting that there is no contribution of methyltransferase to malathion degradation. Among the organophosphorus pesticides with a carboxylester group, only the thion compounds malathion, phenthoate, and methacrifos were enzymatically decomposed by the homogenate. Malathion was also demonstrated to be the substrate of carboxylesterase, as the pesticide competitively inhibited the activity with p-nitrophenyl acetate as the typical substrate. Conversely, oxon organophosphorus pesticides were not degraded in the homogenate, the carboxylesterase of which was noncompetitively inhibited. These results suggest that malathion degradation in wheat kernels is caused by the thion organophosphorus pesticide-specific carboxylesterase.

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Section: Discussionmentioning

confidence: 99%

Section: Malathion Residue In Wheat Kernels Is Degraded By Thion Orgamentioning

confidence: 99%

Malathion Residue in Wheat Kernels is Degraded by Thion Organophosphorus Pesticide-Specific Carboxylesterase

Yoshii

Tonogai²,

Ueno

et al. 2006

JOURNAL OF HEALTH SCIENCE

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“…Malathion is an organophosphorothionate pesticide with relative low toxicity, can be activated by the cytochrome P450 system by oxidative desulfuration to form malaoxon, an effective inhibitor of AchE. 23 In the present study, we have explored the effects of a sub chronic exposure of malathion at 27mg/kg bw (1/50 of the oral LD 50 ) for 90days on liver and kidneys toxicities in male rats. Present study showed that sub chronic exposure to malathion was able to induce a significant decrease in body weight, food intake, liver and kidney weights in ML-treated group compared control group.…”

Section: Discussionmentioning

confidence: 99%

Ameliorative Role of Melissa officinalis against Hepatorenal Toxicities of Organophosphorus Malathion in Male Rats

El-Raheem¹

2015

MOJT

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It has been confirmed that organophosphorus compounds OP altered glucose homeostasis. Considerable experimental and clinical evidences have contributed the beneficial effects of antioxidant compounds in plant extract on hepatorenal toxicity. The aim of this study was to evaluate whether Melissa officinalis extract, was able to ameliorative hepatorenal injury induced by organophosphorus Malathion. Malathion at 27mg/kg bw was administered to rats alone or in combination with Melissa officinalis extract at 200mg/kg bw. Malathion decreases feed intake and body weight as well as liver and kidneys weight. Moreover, Malathion increases the levels of various serum marker enzymes AST, ALT and ALP. A significant increase in the level of serum urea, uric acid and creatinine in response to ML treatment. As well as ML induced increase in MDA in liver and kidneys while induced decreases in the activities of SOD, GPx and CAT. Co-administration of malathion with Melissa officinalis extract resulted in restoration of all tested parameter. These results may be due to the significant increase recorded in acetylcholine esterase (Ach E) activity invivo after co administration of malathion and Melissa officinalis extract. In histological study of liver and kidney, Malathion induced damage in liver and kidneys. However, MO administration to ML-treated animals resulted in overall improvement in liver and kidneys damage, emphasizing its antioxidant role. In light of the available data, it can deduce that ML-induced lipid peroxidation, oxidative stress, liver and kidneys damage rats, and conjoint supplementation of MO has resulted in pronounced ameliorating effect in all tested parameter and histological picture of liver and kidney. MOJ Toxicology Research ArticleOpen Access Ameliorative role of melissa officinalis against hepatorenal toxicities of organophosphorus malathion in male rats 104Copyright: ©2015 Sief et al. Citation:Sief MM, Khalil FA, Abou-Arab AA, et al. Ameliorative role of melissa officinalis against hepatorenal toxicities of organophosphorus malathion in male rats.

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“…Microsomal mixed function oxidase is the primary enzyme for the phase I reactions that convert xenobiotics into more soluble products. Although these products are generally less toxic than the parent compound, more toxic metabolites may also occur, as in the cases of parathion (Chambers et al, 1991) and malathion (Buratti et al, 2005). Such in vitro studies with microsomal preparations provide specific details of the chemical identity of metabolites and intermediates, the pattern of their formation, and the metabolic pathways of xenobiotics (Liu et al, 2002;Liu and Kim, 2003;Kim et al, 2005a).…”

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confidence: 99%

Stereoselective Metabolism of Endosulfan by Human Liver Microsomes and Human Cytochrome P450 Isoforms

Lee

Moon²,

Chang³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Endosulfan (6,7,8,9,10,10-hexachloro-1,5,5a,6,9,9a-hexahydro-6,9-methano-2,3,4-benzo(e)dioxathiepin-3-oxide) is a broad-spectrum chlorinated cyclodiene insecticide. This study was performed to elucidate the stereoselective metabolism of endosulfan in human liver microsomes and to characterize the cytochrome P450 (P450) enzymes that are involved in the metabolism of endosulfan. Human liver microsomal incubation of endosulfan in the presence of NADPH resulted in the formation of the toxic metabolite, endosulfan sulfate. The intrinsic clearances (CL int ) of endosulfan sulfate from ␤-endosulfan were 3.5-fold higher than those from ␣-endosulfan, suggesting that ␤-endosulfan would be cleared more rapidly than ␣-endosulfan. Correlation analysis between the known P450 enzyme activities and the rate of the formation of endosulfan sulfate in the 14 human liver microsomes showed that ␣-endosulfan metabolism is significantly correlated with CYP2B6-mediated bupropion hydroxylation and CYP3A-mediated midazolam hydroxylation, and that ␤-endosulfan metabolism is correlated with CYP3A activity. The P450 isoform-selective inhibition study in human liver microsomes and the incubation study of cDNA-expressed enzymes also demonstrated that the stereoselective endosulfan sulfate formation from ␣-endosulfan is mediated by CYP2B6, CYP3A4, and CYP3A5, and that from ␤-endosulfan is mediated by CYP3A4 and CYP3A5. The total CL int values of endosulfan sulfate formation catalyzed by CYP3A4 and CYP3A5 were consistently higher for ␤-endosulfan than for the ␣-form (CL int of 0.67 versus 10.46 l/min/pmol P450, respectively). CYP2B6 stereoselectively metabolizes ␣-endosulfan, but not ␤-endosulfan. These findings suggest that the CYP2B6 and CYP3A enzymes are major enzymes contributing to the stereoselective disposition of endosulfan.

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Malathion Bioactivation in the Human Liver: The Contribution of Different Cytochrome P450 Isoforms

Cited by 105 publications

References 36 publications

Malathion Residue in Wheat Kernels is Degraded by Thion Organophosphorus Pesticide-Specific Carboxylesterase

Malathion Residue in Wheat Kernels is Degraded by Thion Organophosphorus Pesticide-Specific Carboxylesterase

Ameliorative Role of Melissa officinalis against Hepatorenal Toxicities of Organophosphorus Malathion in Male Rats

Stereoselective Metabolism of Endosulfan by Human Liver Microsomes and Human Cytochrome P450 Isoforms

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