Metabolism of Anethole Dithiolethione by Rat and Human Liver Microsomes: Formation of Various Products Deriving from Its -Demethylation and -Oxidation. Involvement of Cytochromes P450 and Flavin Monooxygenases in These Pathways.

Drug Metab Dispos

Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR 8601, University Paris Descartes, Paris, France (M.D., A.S., C.N., P.D., D.M., J.-L.B.) and Marie-Odile Christen Behavior, Paris, France (M.-O.C.)

Published: October 2018

A study of the metabolism of anethole dithiolethione (ADT, 5-(p-methoxyphenyl)-3-1,2-dithiole-3-thione) by rat and human liver microsomes showed the formation of the corresponding -oxide and the -oxide of desmethyl-ADT (dmADT, 5-(p-hydroxyphenyl)-3-1,2-dithiole-3-thione), and of p-methoxy-acetophenone (pMA) and p-hydroxy-acetophenone (pHA), in addition to the previously described metabolites, dmADT, anethole dithiolone (ADO, 5-(p-methoxyphenyl)-3-1,2-dithiole-3-one) and its demethylated derivative dmADO [5-(p-hydroxyphenyl)-3-1,2-dithiole-3-one]. The microsomal metabolism of ADO under identical conditions led to dmADO and to pMA and pHA. The metabolites of ADT derive from two competing oxidative pathways: an -demethylation catalyzed by cytochromes P450 and an -oxidation mainly catalyzed by flavin-dependent monooxygenases (FMO) and, to a minor extent, by CYP enzymes. The most active human CYP enzymes for ADT demethylation appeared to be CYP1A1, 1A2, 1B1, 2C9, 2C19, and 2E1. ADT -oxidation is catalyzed by FMO 1 and 3, and to a minor extent by CYP enzymes such as CYP3A4.

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http://dx.doi.org/10.1124/dmd.118.082545DOI Listing

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