Comparison of Various Aryl-Dithiolethiones and Aryl-Dithiolones As Hydrogen Sulfide Donors in the Presence of Rat Liver Microsomes.

It has been reported that microsomal metabolism of ADT (5-(p-methoxyphenyl)-3H-1,2-dithiole-3-thione, anetholedithiolethione, Sulfarlem) and ADO (5-(p-methoxyphenyl)-3H-1,2-dithiole-3-one, anetholedithiolone) led to formation of HS mainly derived from oxidations catalyzed by cytochrome P450-dependent monooxygenases and that ADO was a better HS donor than ADT under these conditions. This article compares the HS donor abilities of 18 dithiolethione and dithiolone analogs of ADT and ADO upon incubation with rat liver microsomes. It shows that, for all the studied compounds, maximal HS formation was obtained after incubation with microsomes and NADPH and that this formation greatly decreased in the presence of -benzylimidazole, a known inhibitor of cytochrome P450. This indicates that HS formation from all the studied compounds requires, as previously observed in the case of ADT and ADO, oxidations catalyzed by cytochrome P450-dependent monooxygenases. Under these conditions, the studied dithiolones were almost always better HS donors than the corresponding dithiolethiones. Interestingly, the best HS 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 HS were formed in microsomal incubations of those compounds with 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 5-(p-methoxyphenyl)-3H-1,2-dithiole-3-one-1-sulfoxide, the ADO metabolite involved in HS formation in microsomal oxidation of ADO. SIGNIFICANCE STATEMENT: A series of 18 dithiolethiones and dithiolones were compared for their ability to form hydrogen sulfide (HS) in oxidations catalyzed by microsomal monooxygenases. The studied dithiolones were better HS donors than the corresponding dithiolethiones, and the addition of glutathione to the incubations strongly increased HS 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.