Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR 8601, University Paris Descartes, Paris, France.
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR 8601, University Paris Descartes, Paris, France
Drug Metab Dispos. 2020 Jun;48(6):426-431. doi: 10.1124/dmd.119.090274. Epub 2020 Mar 31.
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.
据报道，ADT（5-（对甲氧基苯基）-3H-1,2-二硫杂环戊-3-硫酮，茴香硫醚二硫酮）和 ADO（5-（对甲氧基苯基）-3H-1,2-二硫杂环戊-3-酮，茴香硫醚二硫醇酮）的微粒体代谢导致 HS 的形成主要来源于细胞色素 P450 依赖性单加氧酶催化的氧化，并且在这些条件下，ADO 是比 ADT 更好的 HS 供体。本文比较了 18 种 ADT 和 ADO 的二硫代噻唑啉和二硫代噻唑酮类似物在与大鼠肝微粒体孵育时的 HS 供体能力。结果表明，对于所有研究的化合物，在用微粒体和 NADPH 孵育后获得最大 HS 形成，并且在存在已知的细胞色素 P450 抑制剂 - 苯并咪唑时，这种形成大大减少。这表明 HS 的形成所有研究的化合物都需要细胞色素 P450 依赖性单加氧酶催化的氧化，如先前在 ADT 和 ADO 的情况下观察到的那样。在这些条件下，研究的二硫代噻唑酮通常比相应的二硫代噻唑啉更好的 HS 供体。有趣的是，在存在谷胱甘肽 (GSH) 的情况下，在 ADO 及其类似物 pCl-Ph-DO 和 Ph-DO 的微粒体氧化中观察到高达 75%的最佳 HS 产率，而在用 GSH 但不存在 NADPH 孵育那些化合物时仅形成少量 HS。基于从 GSH 与 5-（对甲氧基苯基）-3H-1,2-二硫杂环戊-3-酮-1-亚砜的反应中获得的结果，提出了这种 GSH 效应的可能机制，5-（对甲氧基苯基）-3H-1,2-二硫杂环戊-3-酮-1-亚砜是 ADO 在 ADO 微粒体氧化中形成 HS 的代谢物。意义陈述：比较了一系列 18 种二硫代噻唑啉和二硫代噻唑酮，以比较它们在微粒体单加氧酶催化的氧化中形成硫化氢 (HS) 的能力。研究的二硫代噻唑酮比相应的二硫代噻唑啉更好的 HS 供体，并且向孵育物中添加谷胱甘肽强烈增加了 HS 的形成。基于从 GSH 与 5-（对甲氧基苯基）-3H-1,2-二硫杂环戊-3-酮-1-亚砜的反应中获得的结果，提出了这种 GSH 效应的可能机制，5-（对甲氧基苯基）-3H-1,2-二硫杂环戊-3-酮-1-亚砜是 ADO 在 ADO 微粒体氧化中形成 HS 的代谢物。
