Mechanism of H 2 S Formation from the Metabolism of Anetholedithiolethione and Anetholedithiolone by Rat Liver Microsomes
Résumé
The drug anetholedithiolethione, ADT, and its analogs have been extensively used as H2S donors. However, the mechanism of H2S formation from ADT under biological conditions remains almost completely unknown. This article shows that incubation of ADT or its metabolite anetholedithiolone, ADO, with rat liver microsomes, leads to H2S in the presence of NADPH and O2, and that H2S formation is greatly inhibited by N-benzyl-imidazole, indicating that this formation is mainly catalyzed by cytochrome P450-dependent monooxygenases. It also shows that there is a concomitant formation of H2S and para-methoxy-acetophenone, pMA, during microsomal metabolism of ADT and ADO. This article shows for the first time that ADO is a better H2S donor than ADT under those conditions, and proposes first detailed mechanisms for the formation of H2S from the microsomal metabolism of ADT and ADO.