S-oxygenation of N-substituted thioureas catalyzed by the pig liver microsomal FAD-containing monooxygenase

Poulsen, Lawrence L.; Hyslop, Richard M.; Ziegler, Daniel M.

doi:10.1016/0003-9861(79)90397-7

Cited by 132 publications

(83 citation statements)

References 22 publications

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“…Our medicinal chemistry strategy was also weighted Apart from peroxidases, enzymatic bioactivation of thioureas and related analogs (e.g., thiones, thiocarbamides, etc.) to electrophilic intermediates by mammalian P450 and/or FMO isoforms can also lead to toxicity (Poulsen et al, 1979;Neal and Halpert, 1982;Decker and Doerge, 1992;Onderwater et al, 1999Onderwater et al, , 2004Smith and Crespi, 2002;Henderson et al, 2004;Ji et al, 2007). For instance, the cases of clinical hepatotoxicity and/or nephrotoxicity that were noted with the antithyroid drug methimazole (Martinez-Lopez et al, 1962) and the antiparasitic agent thiabendazole (Manivel et al, 1987) have been causally linked with their metabolism to the proximal toxicants N-methylthiourea and thioformamide, respectively, via an initial P450-catalyzed oxidative ring scission of the 2-mercaptobenzimidazole and thiazole motifs present in these drugs.…”

Section: Discussionmentioning

confidence: 99%

“…The initial oxygenation of the sulfur atom produces the electrophilic sulfenic acid (R-SOH) species that is capable of reacting with nucleophiles, including GSH (Poulsen et al, 1979;Neal and Halpert, 1982;Krieter et al, 1984;Decker and Doerge, 1992;Onderwater et al, 1999;Kim and Ziegler, 2000;Smith and Crespi, 2002;Henderson et al, 2004). The sulfenic acid derivatives can undergo redox cycling in the presence of GSH coupled with the oxidation of GSH to GSSG.…”

Section: Discussionmentioning

confidence: 99%

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Species Differences in the Oxidative Desulfurization of a Thiouracil-Based Irreversible Myeloperoxidase Inactivator by Flavin-Containing Monooxygenase Enzymes

Eng

Sharma

Wolford

et al. 2016

Drug Metabolism and Disposition

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N1-Substituted-6-arylthiouracils, represented by compound 1 [6-(2,4-dimethoxyphenyl)-1-(2-hydroxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one], are a novel class of selective irreversible inhibitors of human myeloperoxidase. The present account is a summary of our in vitro studies on the facile oxidative desulfurization in compound 1 to a cyclic ether metabolite M1 [5-(2,4-dimethoxyphenyl)-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-7-one] in NADPH-supplemented rats (t 1/2 [half-life = mean 6 S.D.] = 8.6 6 0.4 minutes) and dog liver microsomes (t 1/2 = 11.2 6 0.4 minutes), but not in human liver microsomes (t 1/2 > 120 minutes). The in vitro metabolic instability also manifested in moderate-to-high plasma clearances of the parent compound in rats and dogs with significant concentrations of M1 detected in circulation. Mild heat deactivation of liver microsomes or coincubation with the flavin-containing monooxygenase (FMO) inhibitor imipramine significantly diminished M1 formation. In contrast, oxidative metabolism of compound 1 to M1 was not inhibited by the pan cytochrome P450 inactivator 1-aminobenzotriazole. Incubations with recombinant FMO isoforms (FMO1, FMO3, and FMO5) revealed that FMO1 principally catalyzed the conversion of compound 1 to M1. FMO1 is not expressed in adult human liver, which rationalizes the species difference in oxidative desulfurization. Oxidation by FMO1 followed Michaelis-Menten kinetics with Michaelis-Menten constant, maximum rate of oxidative desulfurization, and intrinsic clearance values of 209 mM, 20.4 nmol/min/mg protein, and 82.7 ml/min/mg protein, respectively. Addition of excess glutathione essentially eliminated the conversion of compound 1 to M1 in NADPH-supplemented rat and dog liver microsomes, which suggests that the initial FMO1-mediated S-oxygenation of compound 1 yields a sulfenic acid intermediate capable of redox cycling to the parent compound in a glutathionedependent fashion or undergoing further oxidation to a more electrophilic sulfinic acid species that is trapped intramolecularly by the pendant alcohol motif in compound 1.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Species Differences in the Oxidative Desulfurization of a Thiouracil-Based Irreversible Myeloperoxidase Inactivator by Flavin-Containing Monooxygenase Enzymes

Eng

Sharma

Wolford

et al. 2016

Drug Metabolism and Disposition

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“…The rapid enzymatic oxidation of thiourea derivatives is known to be catalyzed by the mammalian FMO enzymes (24,25). However, both the structure/function properties of EtaA, the FMO from M. tuberculosis, and the physiological functions of this enzyme are still largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Oxidative Activation of Thiacetazone by the Mycobacterium tuberculosis Flavin Monooxygenase EtaA and Human FMO1 and FMO3

Qian

Montellano

2006

Chem. Res. Toxicol.

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Thiacetazone (TAZ) and ethionamide (ETA) are, respectively, thiourea and thioamide-containing second line antitubercular prodrugs for which there is an extensive clinical history of cross-resistance in Mycobacterium tuberculosis. EtaA, a recently identified flavin-containing monooxygenase (FMO), is responsible for the oxidative activation of ETA in M. tuberculosis. We report here that EtaA also oxidizes TAZ and identify a sulfinic acid and a carbodiimide as the isolable metabolites. Both of these metabolites are derived from an initial sulfenic acid intermediate. Oxidation of TAZ by EtaA at basic pH favors formation of the carbodiimide, whereas neutral or acidic conditions favor formation of the sulfinic acid. The same metabolites are formed from TAZ by human FMO1 and FMO3. The sulfenic acid and carbodiimide metabolites, but not the sulfinic acid product, readily react with glutathione, the first to regenerate the parent drug and the second to give a glutathione adduct. These reactions that may contribute to the antitubercular activity and/or toxicity of TAZ.

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“…This compound is known to have a very high affinity for mammalian flavin-containing monooxygenase and to be selectively oxidized by this enzymatic system in the presence of cytochrome P-450 (23,24). It has thus been used as an alternate substrate in hepatic microsomes that contain both types of monooxygenases to discriminate between reactions catalyzed by flavin-containing monooxygenase and cytochrome P-450 (13,17). Even though the substrate specificity of bacterial flavin-containing monooxygenase is not well defined, this enzyme is known to oxidize soft nucleophiles such as amines and alkyl or aryl sulfides and phenolic compounds (24).…”

Section: Vol 177 1995mentioning

confidence: 99%

Metabolism of polychlorinated phenols by Pseudomonas cepacia AC1100: determination of the first two steps and specific inhibitory effect of methimazole

et al. 1995

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Resting cells of 2,4,5-trichlorophenoxyacetic acid-grown Pseudomonas cepacia AC1100 metabolize both dichlorophenols, such as 2,4-dichlorophenol, 2,6-dichlorophenol, 3,4-dichlorophenol, and 3,5-dichlorophenol, and more highly substituted phenols, such as 2,4,6-trichlorophenol and pentachlorophenol, to the corresponding chlorohydroquinones. The first hydroxylation occurs in the para position of the phenol regardless of whether this position is replaced by a chlorine substituent. The first evidence leading to the characterization of para-hydroxylase as a flavin-containing enzyme is provided by the inhibitory effect of methimazole, an alternate substrate for this monooxygenase, on the degradative ability of the strain. In a second step, with tetrachlorohydroquinone, trichlorohydroxyquinone was isolated and completely characterized. Trichlorohydroxyquinone was also obtained from tetrachloroquinone. Incubation of the cells in the presence of an external source of NADPH prevents the further degradation of tetrachlorohydroquinone, suggesting that the quinone derived from the two-electron oxidation of the hydroquinone is more likely the substrate for the second hydroxylation.

show abstract

S-oxygenation of N-substituted thioureas catalyzed by the pig liver microsomal FAD-containing monooxygenase

Cited by 132 publications

References 22 publications

Species Differences in the Oxidative Desulfurization of a Thiouracil-Based Irreversible Myeloperoxidase Inactivator by Flavin-Containing Monooxygenase Enzymes

Species Differences in the Oxidative Desulfurization of a Thiouracil-Based Irreversible Myeloperoxidase Inactivator by Flavin-Containing Monooxygenase Enzymes

Oxidative Activation of Thiacetazone by the Mycobacterium tuberculosis Flavin Monooxygenase EtaA and Human FMO1 and FMO3

Metabolism of polychlorinated phenols by Pseudomonas cepacia AC1100: determination of the first two steps and specific inhibitory effect of methimazole

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