Abstract
A study of the metabolism of anethole dithiolethione (ADT) by rat and human liver microsomes showed the formation of the corresponding S-oxide and the S-oxide of desmethyl-ADT (dmADT), and of p-methoxy-acetophenone (pMA) and p-hydroxy-acetophenone (pHA), in addition to the previously described metabolites, dmADT, anethole dithiolone (ADO) and its demethylated derivative, dmADO. 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 O-demethylation catalyzed by cytochromes P450 (CYPs) and an S-oxidation mainly catalyzed by flavin-dependent monooxygenases (FMOs) and, to a minor extent, by CYPs. The most active human CYPs for ADT demethylation appeared to be CYP1A1, 1A2, 1B1, 2C9, 2C19 and 2E1. ADT S-oxidation is catalyzed by FMOs 1 and 3, and, to a minor extent, by CYPs such as CYP3A4.
- The American Society for Pharmacology and Experimental Therapeutics