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.118.082545 | DOI Listing |
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