Qian Lian, Ortiz de Montellano Paul R
Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, California 94143-2280, USA.
Chem Res Toxicol. 2006 Mar;19(3):443-9. doi: 10.1021/tx050328b.
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.
硫乙酰胺（TAZ）和乙硫异烟胺（ETA）分别是含硫脲和硫代酰胺的二线抗结核前体药物，在结核分枝杆菌中存在广泛的交叉耐药临床历史。EtaA是最近鉴定出的一种含黄素单加氧酶（FMO），负责结核分枝杆菌中ETA的氧化激活。我们在此报告EtaA也能氧化TAZ，并鉴定出亚磺酸和碳二亚胺为可分离的代谢产物。这两种代谢产物均源自最初的亚磺酸中间体。在碱性pH条件下，EtaA对TAZ的氧化有利于碳二亚胺的形成，而中性或酸性条件则有利于亚磺酸的形成。人FMO1和FMO3对TAZ的氧化也会生成相同的代谢产物。亚磺酸和碳二亚胺代谢产物，而非亚磺酸产物，能与谷胱甘肽迅速反应，前者使母体药物再生，后者生成谷胱甘肽加合物。这些反应可能有助于TAZ的抗结核活性和/或毒性。
