Thiourea toxicity in mouse C3H/10T12 cells expressing human flavin-dependent monooxygenase 3

Smith, P.Blaise; Crespi, Charles L.

doi:10.1016/s0006-2952(02)00978-4

Cited by 47 publications

(34 citation statements)

References 30 publications

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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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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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“…FMOs bioactivate thioureas through S-oxygenation to toxic sulfenic and/or sulfinic acid metabolites Neal & Halpert, 1982;Ziegler, 1982;Sabourin & Hodgson, 1984;Nagata et al, 1990;Decker & Doerge, 1991;Guo et al, 1992;Kim & Ziegler, 2000;Smith & Crespi, 2002). The sulfenic acid is capable of undergoing redox cycling following conjugation with glutathione, resulting in oxidative stress due to depletion of reduced glutathione and NADPH (Hardwick et al, 1991;Onderwater et al, 1998Onderwater et al, , 1999Onderwater et al, , 2004Smith & Crespi, 2002;Henderson et al, 2004b).…”

Section: Genetic Polymorphisms Of Flavin-containing Monooxygenasementioning

confidence: 99%

“…FMO can S-oxygenate thioureas to sulfenic acids which can undergo redox cycling or be further converted to the reactive sulfinic acid Neal & Halpert, 1982;Ziegler, 1982;Krieter et al, 1984;Sabourin & Hodgson, 1984;Nagata et al, 1990;Decker & Doerge, 1991;Guo & Ziegler, 1991;Guo et al, 1992;Onderwater et al, 1999Onderwater et al, , 2004Kim & Ziegler, 2000;Smith & Crespi, 2002;Henderson et al, 2004b).…”

Section: Introductionmentioning

confidence: 99%

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

Krueger

Williams

2005

Pharmacology & Therapeutics

515

444

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Flavin-containing monooxygenase (FMO) oxygenates drugs and xenobiotics containing a "softnucleophile", usually nitrogen or sulfur. FMO, like cytochrome P450 (CYP), is a monooxygenase, utilizing the reducing equivalents of NADPH to reduce 1 atom of molecular oxygen to water, while the other atom is used to oxidize the substrate. FMO and CYP also exhibit similar tissue and cellular location, molecular weight, substrate specificity, and exist as multiple enzymes under developmental control. The human FMO functional gene family is much smaller (5 families each with a single member) than CYP. FMO does not require a reductase to transfer electrons from NADPH and the catalytic cycle of the 2 monooxygenases is strikingly different. Another distinction is the lack of induction of FMOs by xenobiotics.In general, CYP is the major contributor to oxidative xenobiotic metabolism. However, FMO activity may be of significance in a number of cases and should not be overlooked. FMO and CYP have overlapping substrate specificities, but often yield distinct metabolites with potentially significant toxicological/pharmacological consequences.The physiological function(s) of FMO are poorly understood. Three of the 5 expressed human FMO genes, FMO1, FMO2 and FMO3, exhibit genetic polymorphisms. The most studied of these is FMO3 (adult human liver) in which mutant alleles contribute to the disease known as trimethylaminuria. The consequences of these FMO genetic polymorphisms in drug metabolism and human health are areas of research requiring further exploration.

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“…Although oxygenation usually represents a detoxication reaction, some FMO-oxygenated sulfur substrates, such as thioureas, produce reactive sulfenic or sulfinic acids as major metabolites. Sulfenic acid metabolites can react with GSH inducing oxidative stress through a futile redox cycle [2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Characterization of mouse flavin-containing monooxygenase transcript levels in lung and liver, and activity of expressed isoforms

Siddens

Henderson

VanDyke

et al. 2008

Biochemical Pharmacology

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The significance of active vs. inactive flavin-containing monooxygenase 2 (FMO2) for human drug and xenobiotic metabolism and sensitivity is unknown, but the underlying ethnic polymorphism is well documented. We used quantitative real-time PCR to measure message levels of Fmo1, Fmo2, Fmo3 and Fmo5 in lung and liver from eight strains of eight week old female mice to determine if a strain could be identified that predominately expressed Fmo2 in lung, recapitulating the human FMO expression profile and being the ideal strain for Fmo2 knockout studies. We also characterized enzyme activity of baculovirus expressed mouse Fmo1, Fmo2 and Fmo3 to identify a substrate or incubation conditions capable of discriminating Fmo2 from Fmo mixtures. Fmo transcript expression patterns were similar for all strains. In lung, 59% of total FMO message was Fmo2, but Fmo1 levels were also high, averaging 34%, whereas Fmo3 and Fmo5 levels were 2 and 5%, respectively. In liver, Fmo1, Fmo2, Fmo3 and Fmo5 contributed 16, 1, 7 and 76% respectively, of detected message. Peak activity varied by isoform and was pH-and substrate-dependent. Fmo3 oxidation of methyl ptolyl sulfide was negligible at pH 9.5, but Fmo3 oxidation of methimazole was comparable to Fmo1 and Fmo2. Heating microsomes at 50 °C for 10 min eliminated most Fmo1 and Fmo3 activity, while 94% of Fmo2 activity remained. Measurement of activity in heated and unheated lung and liver microsomes verified relative transcript abundance. Our results show that dual Fmo1/2 knockouts will be required to model the human lung FMO profile.

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Thiourea toxicity in mouse C3H/10T12 cells expressing human flavin-dependent monooxygenase 3

Cited by 47 publications

References 30 publications

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

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

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

Characterization of mouse flavin-containing monooxygenase transcript levels in lung and liver, and activity of expressed isoforms

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