The metabolism of ethionamide and its sulphoxide

Johnston, J. P.; Kane, P. O.; Kibby, Michael R.

doi:10.1111/j.2042-7158.1967.tb07986.x

Cited by 33 publications

(11 citation statements)

References 10 publications

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“…34, 35 Ethionamide (2-ethylisothionicotinamide) and its S -oxide metabolite are likewise readily interconvertible in man, rats, mice and dogs. 36 The back reduction of TASO may have important consequences for the biology of liver injury by TA and TASO. Chilakapati et al 15, 28 administered [ 14 C]-TASO to rats and observed that a 12-fold increase in dose caused only a 2.5-fold increase in covalent binding to liver proteins.…”

Section: Discussionmentioning

confidence: 99%

Metabolism and Toxicity of Thioacetamide and Thioacetamide S-Oxide in Rat Hepatocytes

Hajovsky

Koen

et al. 2012

Chem. Res. Toxicol.

176

142

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The hepatotoxicity of thioacetamide (TA) has been known since 1948. In rats, single doses cause centrilobular necrosis accompanied by increases in plasma transaminases and bilirubin. To elicit these effects TA requires oxidative bioactivation leading first to its S-oxide (TASO) and then to its chemically reactive S,S-dioxide (TASO2) which ultimately modifies amine-lipids and proteins. To generate a suite of liver proteins adducted by TA metabolites for proteomic analysis, and to reduce the need for both animals and labeled compounds, we treated isolated hepatocytes directly with TA. Surprisingly, TA was not toxic at concentrations up to 50 mM for 40 hr. On the other hand, TASO was highly toxic to isolated hepatocytes as indicated by LDH release, cellular morphology and vital staining with Hoechst 33342/propidium iodide. TASO toxicity was partially blocked by the CYP2E1 inhibitors diallyl sulfide and 4-methylpyrazole, and was strongly inhibited by TA. Significantly, we found that hepatocytes produce TA from TASO relatively efficiently by back-reduction. The covalent binding of [14C]-TASO is inhibited by unlabeled TA which acts as a “cold-trap” for [14C]-TA and prevents its re-oxidation to [14C]-TASO. This in turn increases the net consumption of [14C]-TASO despite the fact that its oxidation to TASO2 is inhibited. The potent inhibition of TASO oxidation by TA, coupled with the back-reduction of TASO and its futile redox cycling with TA may help explain phenomena previously interpreted as “saturation toxicokinetics” in the in vivo metabolism and toxicity of TA and TASO. The improved understanding of the metabolism and covalent binding of TA and TASO facilitates the use of hepatocytes to prepare protein adducts for target protein identification.

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Section: Discussionmentioning

confidence: 99%

Metabolism and Toxicity of Thioacetamide and Thioacetamide S-Oxide in Rat Hepatocytes

Hajovsky

Koen

et al. 2012

Chem. Res. Toxicol.

176

142

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“…Although activated ETA has been shown to share a common molecular target with INH, KatG mutants resistant to INH retain their sensitivity toward ETA, suggesting that ETA activation requires an entirely different enzyme. It has long been known that in vivo ETA demonstrates more consistent antitubercular activity than one would expect from in vitro examination of its minimal inhibitory concentration (MIC), and it has been demonstrated that a major metabolite of ETA in vivo is its S-oxide (2), which shows comparable in vitro activity (18)(19)(20)(21)(22). A wide variety of toxic thiocarbonyl-containing compounds have been shown to be converted to the corresponding S-oxides during in vivo metabolism by mammals supporting this as an intermediate oxidation in the metabolic activation of ETA (23).…”

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confidence: 99%

Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis

DeBarber

Mdluli

Bosman

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

309

335

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Ethionamide (ETA) is an important component of second-line therapy for the treatment of multidrug-resistant tuberculosis. Synthesis of radiolabeled ETA and an examination of drug metabolites formed by whole cells of Mycobacterium tuberculosis (MTb) have allowed us to demonstrate that ETA is activated by Soxidation before interacting with its cellular target. ETA is metabolized by MTb to a 4-pyridylmethanol product remarkably similar in structure to that formed by the activation of isoniazid by the catalase-peroxidase KatG. We have demonstrated that overproduction of Rv3855 (EtaR), a putative regulatory protein from MTb, confers ETA resistance whereas overproduction of an adjacent, clustered monooxygenase (Rv3854c, EtaA) confers ETA hypersensitivity. Production of EtaA appears to be negatively regulated by EtaR and correlates directly with [ 14 C]ETA metabolism, suggesting that EtaA is the activating enzyme responsible for thioamide oxidation and subsequent toxicity. Coding sequence mutations in EtaA were found in 11 of 11 multidrug-resistant MTb patient isolates from Cape Town, South Africa. These isolates showed broad cross-resistance to thiocarbonyl containing drugs including ETA, thiacetazone, and thiocarlide.

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“…3A) (Vannelli et al, 2002). Assessment of biologic activity of the S-oxide metabolites showed that this metabolite retained full activity of ethionamide against Mycobacterium tuberculosis (Johnston et al, 1967). Similarly, human FMO1 and FMO3 have been shown to catalyze the oxidative activation of thiacetazone to isolable sulfinic acid and carbodiimide metabolites (Fig.…”

Section: Flavin-containing Monooxygenasesmentioning

confidence: 99%

Cytochrome P450 and Non-Cytochrome P450 Oxidative Metabolism: Contributions to the Pharmacokinetics, Safety, and Efficacy of Xenobiotics

Foti

Dalvie

2016

Drug Metabolism and Disposition

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The drug-metabolizing enzymes that contribute to the metabolism or bioactivation of a drug play a crucial role in defining the absorption, distribution, metabolism, and excretion properties of that drug. Although the overall effect of the cytochrome P450 (P450) family of drug-metabolizing enzymes in this capacity cannot be understated, advancements in the field of non-P450-mediated metabolism have garnered increasing attention in recent years. This is perhaps a direct result of our ability to systematically avoid P450 liabilities by introducing chemical moieties that are not susceptible to P450 metabolism but, as a result, may introduce key pharmacophores for other drug-metabolizing enzymes. Furthermore, the effects of both P450 and non-P450 metabolism at a drug's site of therapeutic action have also been subject to increased scrutiny. To this end, this Special Section on Emerging Novel Enzyme Pathways in Drug Metabolism will highlight a number of advancements that have recently been reported. The included articles support the important role of non-P450 enzymes in the clearance pathways of U.S. Food and Drug Administration-approved drugs over the past 10 years. Specific examples will detail recent reports of aldehyde oxidase, flavin-containing monooxygenase, and other non-P450 pathways that contribute to the metabolic, pharmacokinetic, or pharmacodynamic properties of xenobiotic compounds. Collectively, this series of articles provides additional support for the role of non-P450-mediated metabolic pathways that contribute to the absorption, distribution, metabolism, and excretion properties of current xenobiotics.

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The metabolism of ethionamide and its sulphoxide

Cited by 33 publications

References 10 publications

Metabolism and Toxicity of Thioacetamide and Thioacetamide S-Oxide in Rat Hepatocytes

Metabolism and Toxicity of Thioacetamide and Thioacetamide S-Oxide in Rat Hepatocytes

Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis

Cytochrome P450 and Non-Cytochrome P450 Oxidative Metabolism: Contributions to the Pharmacokinetics, Safety, and Efficacy of Xenobiotics

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