Sulfoxidation of thioether-containing pesticides by the flavin-adenine dinucleotide-dependent monooxygenase of pig liver microsomes

Hajjar, Nicolas P.; Hodgson, Ernest

doi:10.1016/0006-2952(82)90458-0

Cited by 61 publications

(15 citation statements)

References 23 publications

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“…Previous studies of pesticide metabolism in rodents have demonstrated that phorate, disulfoton, sulprofos, and methiocarb were good substrates for FMO activity (Hajjar and Hodgson, 1982;Kinsler et al, 1988;Buronfosse et al, 1995). Our results confirm a role for FMO in these pesticide sulfoxidations in humans and further identify FMO1 as…”

Section: Usmani Et Alsupporting

confidence: 86%

In Vitro Sulfoxidation of Thioether Compounds by Human Cytochrome P450 and Flavin-Containing Monooxygenase Isoforms With Particular Reference to the Cyp2c Subfamily

Usmani

Karoly²,

Hodgson³

et al. 2004

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Cytochrome P450 (P450) and flavin-containing monooxygenase (FMO) enzymes are major catalysts involved in the metabolism of xenobiotics. The sulfoxidation of the thioether pesticides, phorate, disulfoton, sulprofos, and methiocarb, was investigated. Using pooled human liver microsomes (HLMs), thioether compounds displayed similar affinities; however, phorate and disulfoton displayed higher intrinsic clearance rates than either sulprofos or methiocarb. The sulfoxidation of thioethers by HLMs was found to be predominantly P450-driven (85-90%) compared with FMO (10-15%). Among 16 cDNA-expressed human P450 isoforms and 3 human FMO isoforms examined, the following isoforms and their polymorphisms had the highest rates for sulfoxidation, as follows: phorate, CYP1A2, 3A4, 2B6, 2C9*1, 2C18, 2C19, 2D6*1, and FMO1; disulfoton, CYP1A2, 3A4, 2B6, 2C9*1, 2C9*2, 2C18, 2C19, 2D6*1, and FMO1; sulprofos, CYP1A1, 1A2, 3A4, 2C9*1, 2C9*2, 2C9*3, 2C18, 2C19, 2D6*1, and FMO1; methiocarb, CYP1A1, 1A2, 3A4, 2B6, 2C9*1, 2C19, 2D6*1, and FMO1. Among these isoforms, members of the CYP2C subfamily often had the highest affinities and clearance rates. Moreover, sulfaphenazole, a CYP2C9 competitive inhibitor, inhibited disulfoton sulfoxidation by CYP2C9 (IC 50 0.84 M) as well as in HLMs. Ticlopidine, a CYP2C19 mechanism-based inhibitor, inhibited disulfoton sulfoxidation by CYP2C19 (IC 50 after coincubation, 43.5 M; IC 50 after preincubation, 4.3 M) and also in HLMs. Our results indicate that current models of the substrate binding site of the CYP2C subfamily would not effectively predict thioether pesticide metabolism. Thus, the substrate specificity of CYP2Cs is more extensive than is currently believed, and some reevaluation of structure-activity relationships may be required.

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Section: Usmani Et Alsupporting

confidence: 86%

In Vitro Sulfoxidation of Thioether Compounds by Human Cytochrome P450 and Flavin-Containing Monooxygenase Isoforms With Particular Reference to the Cyp2c Subfamily

Usmani

Karoly²,

Hodgson³

et al. 2004

Drug Metab Dispos

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“…The major metabolism reaction of these pesticides in rats, 25) pigs 26) and insects 27) is the oxygenation of sulfur atom to sulfoxide and a further step to sulfone (O=S=O) by cytochrome P450. Fenthion sulfone was also determined in plants.…”

Section: Photolysis Products Of Fenthion and Disulfotonmentioning

confidence: 99%

Comparative Photodegradation Study of Fenthion and Disulfoton under Irradiation of Different Light Sources in Liquid- and Solid-Phases

Hirahara

Ueno

Nakamuro

2001

JOURNAL OF HEALTH SCIENCE

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To assess the photodegradation extent of the organophosphorus pesticides, fenthion and disulfoton in the environment, degradation rates of their chemicals under irradiation by visible light and each region of the ultraviolet (UV) sources, UVA (320-400 nm radiation), UVB (280-320 nm radiation) and UVC (250-260 nm radiation) in liquid-and solid-phases were determined and their photolysis products identified. Although visible light did not cause photodegradation of either fenthion or disulfoton even after the maximal irradiation of 8 hr in both phases, all the ranges of UV sources resulted in the photolysis of both pesticides, despite the solid-phase. The photolysis rates of fenthion under UVB and UVC irradiation in both phases were higher than that under UVA irradiation and also exceeded all of the degradation rates of disulfoton. This confirms that fenthion is more readily degraded than disulfoton in the UVB range. Fenthion sulfoxide and disulfoton sulfoxide were identified as oxidative photolysis products whose photolysis rates were considerably slower than parent compounds, and the oxidation reaction of both pesticides in the liquid-phase was superior to those on the solid-phase, indicating that dissolved oxygen in water is an important factor affecting the photolysis. These results suggest that fenthion in the environment is more rapidly degraded by UVB irradiation in natural sunlight than disulfoton, and sulfoxides of both pesticides remain stable as a photolysis product in the environment.

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“…The flavin-containing monooxygenases (FMOs 1 ) (E.C.1.14.13.8) constitute a family of FAD-, NADPH-, and O 2 -dependent microsomal enzymes that catalyze the oxygenation of many nitrogen-, sulfur-, phosphorous-, selenium-, and other nucleophilic heteroatom-containing chemicals (Ziegler, 1980), drugs (Cashman, 1995), and agrichemicals (Hajjar and Hodgson, 1982). There are as many as six forms of mammalian FMO, and some can be present in multiple tissues of the same organism.…”

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Interindividual Differences of Human Flavin-Containing Monooxygenase 3: Genetic Polymorphisms and Functional Variation

Cashman¹,

Zhang²

2002

Drug Metab Dispos

101

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ABSTRACT:The human flavin-containing monooxygenase (form 3) (FMO3) participates in the oxygenation of nucleophilic heteroatom-containing drugs, xenobiotics, and endogenous materials. Currently, six forms of the FMO gene are known, but it is FMO3 that is the major form in adult human liver that is likely responsible for the majority of FMO-mediated metabolism. The substrate structural feature requirements for human FMO3 is beginning to become known to a greater extent and a few chemicals extensively metabolized by FMO3 have been reported. Expression of FMO3 is species-and tissue-specific, but unlike human cytochrome P450, mammalian FMO3 does not appear to be inducible. Interindividual variation in FMO3-dependent metabolism of drugs, chemicals, and endogenous material is therefore more likely due to genetic effects and not environmental ones. Examples of such interindividual variation come from the study of very rare mutations of the human The flavin-containing monooxygenases (FMOs 1 ) (E.C.1.14.13.8) constitute a family of FAD-, NADPH-, and O 2 -dependent microsomal enzymes that catalyze the oxygenation of many nitrogen-, sulfur-, phosphorous-, selenium-, and other nucleophilic heteroatom-containing chemicals (Ziegler, 1980), drugs (Cashman, 1995), and agrichemicals (Hajjar and Hodgson, 1982). There are as many as six forms of mammalian FMO, and some can be present in multiple tissues of the same organism. Some of this information has been previously summarized (Cashman, 2002a). In humans, there is considerable interindividual and interethnic variability in the levels of FMO. In the past few years, a considerable increase in our understanding of the genetic variability of human FMO has occurred and a summary of the current picture focusing on FMO3 will be presented.Evidence for five functional forms of human FMO exist, each encoded by its own gene, that exhibit between 50 to 58% amino acid identity across species lines (Lawton et al., 1994). With the deposit of FMO6 into GenBank, an analysis of the protein encoded by this gene revealed that this protein shares 70% amino acid sequence identity with human FMO3, however, no function for this gene has been described. The description of multiple forms of FMO was advanced by elucidation of the primary sequences by amino acid (Ozols, 1990;Korsmeyer et al., 1998) and nucleotide analysis Lawton et al., 1994;Phillips et al., 1995). As human FMOs were discovered, the common names assigned to enzymes were formalized and a nomenclature was adopted Lawton et al., 1994). The nomenclature was developed on the basis of nucleotide sequence identity. If a human FMO gene has a sequence with Ն82% identity, it is grouped within a family, and the family is indicated by the first numeral of the designation (i.e., 1, 2, 3. . .). The order of naming followed the chronology of publication of the sequence for each member of the family (Dolphin et al., 1997b). The italicized prefix "FMO" is used to designate the gene or an allelic variant. Allelic variants have been observed for FMO that usu...

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Sulfoxidation of thioether-containing pesticides by the flavin-adenine dinucleotide-dependent monooxygenase of pig liver microsomes

Cited by 61 publications

References 23 publications

In Vitro Sulfoxidation of Thioether Compounds by Human Cytochrome P450 and Flavin-Containing Monooxygenase Isoforms With Particular Reference to the Cyp2c Subfamily

In Vitro Sulfoxidation of Thioether Compounds by Human Cytochrome P450 and Flavin-Containing Monooxygenase Isoforms With Particular Reference to the Cyp2c Subfamily

Comparative Photodegradation Study of Fenthion and Disulfoton under Irradiation of Different Light Sources in Liquid- and Solid-Phases

Interindividual Differences of Human Flavin-Containing Monooxygenase 3: Genetic Polymorphisms and Functional Variation

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