Diazinon Is Activated by CYP2C19 in Human Liver

Kappers, Wendela A.; Edwards, Robert J.; Murray, Stephen A.; Boobis, Alan R.

doi:10.1006/taap.2001.9294

Cited by 99 publications

(44 citation statements)

References 16 publications

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“…Moreover, despite the broad range of S-mephenytoin 4Ј-hydroxylation activity expressed in the panel of HLMs tested, there was no correlation with malaoxon formation. Results obtained with other OPTs were controversial: some authors considered the role of CYP2C19 relevant in OPT dearylation rather than in oxon formation (Tang et al, 2001;Vittozzi et al, 2001;; others suggested some involvement only when hepatic content of the CYP2C family is extremely high, with a simultaneous low CYP3A4 level (Mutch et al, 1999), whereas it has been considered as the major catalyst for diazoxon production at high diazinon concentrations (Kappers et al, 2001). However, the lack of a selective chemical inhibitor of either monoclonal anti-CYP2C19 Ab makes it difficult to conclude a role for this isoform, although the whole body of results indicates a scant contribution to malathion bioactivation.…”

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confidence: 99%

“…In recent years a number of papers have been published on the activity of human P450s involved in the biotransformation of some members of the OPT class (Butler and Murray, 1997;Mutch et al, 1999;Kappers et al, 2001;Tang et al, 2001;Vittozzi et al, 2001;Buratti et al, 2002. It has been demonstrated with human liver microsomes and recombinant human P450s that at low pesticide concentrations (Ͻ10 M), azinphos-methyl, chlorpyrifos, diazinon, and parathion are mainly desulfurated by CYP1A2 (Buratti et al, 2002.…”

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confidence: 99%

“…It has been demonstrated with human liver microsomes and recombinant human P450s that at low pesticide concentrations (Ͻ10 M), azinphos-methyl, chlorpyrifos, diazinon, and parathion are mainly desulfurated by CYP1A2 (Buratti et al, 2002. The role of CYP2B6 to total hepatic oxon formation seemed to be relevant in a wide range of pesticide concentrations (Tang et al, 2001;, whereas the contribution of CYP3A4 was significant only at high OPT levels (Mutch et al, 1999;Kappers et al, 2001;Buratti et al, 2002.…”

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confidence: 99%

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

Buratti

D'Aniello²,

Volpe³

et al. 2004

Drug Metab Dispos

104

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ABSTRACT:Among organophosphorothioate (OPT) pesticides, malathion is considered relatively safe for use in mammals. Its rapid degradation by carboxylesterases competes with the cytochrome P450 (P450)-catalyzed formation of malaoxon, the toxic metabolite. However, impurities in commercial formulations are potent inhibitors of carboxylesterase, allowing a dramatic increase in malaoxon formation. Malathion desulfuration has been characterized in human liver microsomes (HLMs) with a method based on acetylcholinesterase inhibition that is able to detect nanomolar levels of oxon. The active P450 isoforms have been identified by means of a multifaceted strategy, including the use of cDNA-expressed human P450s and correlation, immunoinhibition, and chemical inhibition studies in a panel of phenotyped HLMs. HLMs catalyzed malaoxon formation with a high level of variability (>200-fold). One or two components (K mapp1 ‫؍‬ 53-67 M; K mapp2 ‫؍‬ 427-1721 M) were evidenced, depending on the relative specific P450 content. Results from different approaches indicated that, at low malathion concentration, malaoxon formation is catalyzed by CYP1A2 and, to a lesser extent, 2B6, whereas the role of 3A4 is relevant only at high malathion levels. These results are in line with those found with chlorpyrifos, diazinon, azynphos-methyl, and parathion, characterized by the presence of an aromatic ring in the molecule. Since malathion has linear chains as substituents at the thioether sulfur, it can be hypothesized that, independently from the chemical structure, OPTs are bioactivated by the same P450s. These results also suggest that CYP1A2 and 2B6 can be considered as possible metabolic biomarkers of susceptibility to OPT-induced toxic effects at actual human exposure levels.

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confidence: 99%

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confidence: 99%

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

Buratti

D'Aniello²,

Volpe³

et al. 2004

Drug Metab Dispos

104

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“…Human cytochrome P450 2C19 (CYP2C19), an important drug metabolizing enzyme mainly expressed in the liver, plays pivotal roles in the activation or elimination of many therapeutic drugs, endogenous biomolecules, and environmental toxicants, including proton pump inhibitors (e.g., omeprazole, lansoprazole and pantoprazole), antiplatelet drugs (e.g., clopidogrel), anticonvulsants (e.g., phenytoin, methylphenytoin, diazepam, and phenobarbital), antidepressants (e.g., sertraline, citalopram, fluoxetine, and venlafaxine), anti-infective agents (e.g., proguanil, chlorproguanil, and nelfinavir), hormones (e.g., progesterone and testosterone), and pesticides (e.g., chlorpyifos and diazinon) [1][2][3]. Next to CYP3A4/5 that participates in metabolizing 30% of drugs, CYP2C19 is one of the most important hepatic drug metabolizing enzymes (DMEs), participating in the metabolism of 6-10% of clinically prescribed drugs [4].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA hsa-miR-29a-3p modulates CYP2C19 in human liver cells

Green

Tolleson

et al. 2015

Biochemical Pharmacology

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Cytochrome P450 2C19 (CYP2C19) is involved in the metabolism of many drugs. Extensive studies have demonstrated that genetic variants and endogenous and environmental factors play important roles in the expression of CYP2C19. However, the role of microRNAs (miRNAs) in controlling CYP2C19 expression has not been investigated completely. In the present study, we performed in silico analysis to rank putative miRNA/CYP2C19 hybrids with regards to the predicted stabilities of their duplexes and then we applied a series of biochemical and molecular assays to elucidate the underlying functional mechanisms for the regulation of CYP2C19 by miRNAs. In silico analysis indicated that hsa-miR-23a-3p and hsa-miR-29a-3p target the coding region of CYP2C19 with hybrid stabilities of −27.5 kcal/mol and −23.3 kcal/mol, respectively. RNA electrophoresis mobility shift assays showed that both hsa-miR-23a-3p and hsa-miR-29a-3p miRNAs were able to bind directly to their cognate targets in the CYP2C19 transcript. Further, a significant inverse correlation was found between chemically-induced up-regulation of hsamiR-29a-3p and CYP2C19 expression in HepaRG cells. In addition, inverse correlations were also observed in human liver tissue samples between the level of CYP2C19 mRNA expression and both hsa-miR-23a-3p and hsa-miR-29a-3p levels. All these results demonstrated the suppressing role of hsa-miR-29a-3p on CYP2C19 expression.

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“…During Phase I the molecule can be inactivated or on the contrary, attain activity. Diazinon, a frequently applied organophosphate in dogs is metabolised into diazoxon in the liver that is more active and more toxic than the parent molecule (Kappers et al, 2001., Costa, 2006. Certain antibiotics can be metabolised into an other active form, like the veterinary enrofloxacin to ciprofloxacin in dogs (Kung et al, 1993) or ceftiofur to desfuroylceftiofur.…”

Section: Drug Metabolismmentioning

confidence: 99%

Comparative Veterinary Pharmacokinetics

Jerzsele¹

2012

Readings in Advanced Pharmacokinetics - Theory, Methods and Applications

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Diazinon Is Activated by CYP2C19 in Human Liver

Cited by 99 publications

References 16 publications

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

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

MicroRNA hsa-miR-29a-3p modulates CYP2C19 in human liver cells

Comparative Veterinary Pharmacokinetics

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