College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanakro-1, Gwanak-Gu, Seoul, 08826, Republic of Korea.
College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-Ro, Sangnok-Gu, Ansan-Si, Gyeonggi-Do, 15588, Republic of Korea.
Arch Pharm Res. 2023 Mar;46(3):149-159. doi: 10.1007/s12272-023-01438-1. Epub 2023 Mar 10.
Drug repositioning has gained significant attention over the past several years. The anti-rheumatoid arthritis drug auranofin has been investigated for the treatment of other diseases, including liver fibrosis. Because auranofin is rapidly metabolized, it is necessary to identify the active metabolites of auranofin that have detectable levels in the blood and reflect its therapeutic effects. In the present study, we investigated whether aurocyanide as an active metabolite of auranofin, can be used to evaluate the anti-fibrotic effects of auranofin. Incubation of auranofin with liver microsomes showed that auranofin was susceptible to hepatic metabolism. Previously, we found that the anti-fibrotic effects of auranofin are mediated via system x-dependent inhibition of the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Therefore, we tried to identify active metabolites of auranofin based on their inhibitory effects on system x and NLRP3 inflammasome in bone marrow-derived macrophages. Among the seven candidate metabolites, 1-thio-β-D-glycopyrano-sato-S-(triethyl-phosphine)-gold(I) and aurocyanide potently inhibited system x and NLRP3 inflammasome. A pharmacokinetics study on mice detected significant plasma levels of aurocyanide after auranofin administration. Oral administration of aurocyanide significantly prevented thioacetamide-induced liver fibrosis in mice. Moreover, the in vitro anti-fibrotic effects of aurocyanide were assessed in LX-2 cells, where aurocyanide significantly decreased the migratory ability of the cells. In conclusion, aurocyanide is metabolically stable and detectable in plasma, and has inhibitory effects on liver fibrosis, suggesting that it is a potential marker of the therapeutic effects of auranofin.
药物重定位在过去几年中受到了广泛关注。抗风湿关节炎药物金诺芬已被用于治疗其他疾病，包括肝纤维化。由于金诺芬代谢迅速，因此有必要确定金诺芬的活性代谢物，这些代谢物在血液中有可检测水平并反映其治疗效果。在本研究中，我们研究了金诺芬的活性代谢物硫代氰酸金是否可用于评估金诺芬的抗纤维化作用。金诺芬与肝微粒体孵育表明金诺芬易发生肝代谢。先前，我们发现金诺芬的抗纤维化作用是通过系统 x 依赖性抑制 NOD、LRR 和 pyrin 结构域包含蛋白 3 (NLRP3) 炎性体来介导的。因此，我们试图根据其对骨髓来源的巨噬细胞中系统 x 和 NLRP3 炎性体的抑制作用来鉴定金诺芬的活性代谢物。在 7 种候选代谢物中，1-硫代-β-D-吡喃糖基-S-(三乙基膦)-金（I）和硫代氰酸金强烈抑制系统 x 和 NLRP3 炎性体。对小鼠的药代动力学研究在金诺芬给药后检测到明显的血浆硫代氰酸金水平。硫代氰酸金口服给药可显著预防小鼠的乙硫氨酸诱导的肝纤维化。此外，还在 LX-2 细胞中评估了硫代氰酸金的体外抗纤维化作用，硫代氰酸金可显著降低细胞的迁移能力。总之，硫代氰酸金在血浆中代谢稳定且可检测，对肝纤维化具有抑制作用，表明其可能是金诺芬治疗效果的潜在标志物。
