TY - JOUR T1 - Comparison of various aryl-dithiolethiones and aryl-dithiolones as hydrogen sulfide, H2S, donors in the presence of rat liver microsomes JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.119.090274 SP - dmd.119.090274 AU - Madou-Marilyn Dali AU - Patrick M Dansette AU - Daniel Mansuy AU - Jean-Luc Boucher Y1 - 2020/01/01 UR - http://dmd.aspetjournals.org/content/early/2020/03/31/dmd.119.090274.abstract N2 - It has been reported that formation of H2S from the metabolism of anetholedithiolethione (ADT, Sulfarlem) and anetholedithiolone (ADO) by liver microsomes mainly derived from their oxidation by cytochrome P450 (CYP)-dependent monooxygenases, and that ADO was a better H2S-donor than ADT under these conditions. This article compares the H2S-donor abilities of 18 dithiolethione and dithiolone analogs of ADT and ADO in the presence of rat liver microsomes. It shows that, for all the studied compounds, maximal H2S formation was obtained in microsomal incubations in the presence of NADPH, and that this formation greatly decreased in the presence of N-benzyl imidazole (Bz-ImH), an usual inhibitor of CYP. This indicates that H2S formation from all the studied compounds requires, as previously observed in the case of ADT and ADO, oxidations catalyzed by CYP-dependent monooxygenases. Under these conditions, the studied dithiolones were almost always better H2S-donors than the corresponding dithiolethiones. Interestingly, the best H2S yields (up to 75%) were observed in microsomal oxidation of ADO and its close analogs, pCl-Ph-DO and Ph-DO, in the presence of glutathione (GSH), whereas only small amounts of H2S were formed in microsomal incubations of those compounds in the presence of GSH but in the absence of NADPH. A possible mechanism for this effect of GSH is proposed on the basis of results obtained from reactions of GSH with ADOSO (ADO sulfoxide), the ADO metabolite involved in H2S formation in microsomal oxidation of ADO.SIGNIFICANCE STATEMENT A series of 18 dithiolethiones and dithiolones was compared for their ability to form hydrogen sulphide (H2S) in oxidations catalyzed by microsomal monooxygenases. The studied dithiolones were better H2S-donors than the corresponding dithiolethiones and the addition of glutathione to the incubations strongly increased H2S formation. A possible mechanism for this effect of GSH is proposed on the basis of results obtained from reactions of GSH with 5-(p-methoxyphenyl)-3H-1,2-dithiole-3-one-1-sulfoxide, a metabolite of the choleretic and sialologic drug Sulfarlem. ER -