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Oxidative activation of thiacetazone by the Mycobacterium tuberculosis flavin monooxygenase EtaA and human FMO1 and FMO3.

Abstract：

: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 may contribute to the antitubercular activity and/or toxicity of TAZ.

journal_name

Chem Res Toxicol

journal_title

Chemical research in toxicology

authors

Qian L,Ortiz de Montellano PR

doi

10.1021/tx050328b

subject

Has Abstract

pub_date

2006-03-01 00:00:00

pages

443-9

issue

3

eissn

0893-228X

issn

1520-5010

journal_volume

19

pub_type

杂志文章

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