School of Pharmaceutical Science and Technology, Health Sciences Platform, Tianjin University, Tianjin 30072, China.
Freie Universitaet Berlin, Institute of Pharmacy, Pharmaceutical and Medicinal Chemistry (Pharmaceutical Analyses), Berlin, Germany.
Biol Chem. 2019 Apr 24;400(5):625-628. doi: 10.1515/hsz-2018-0379.
The human cytochrome P450 enzyme CYP8B1 is a crucial regulator of the balance of cholic acid (CA) and chenodeoxycholic acid (CDCA) in the liver. It was previously shown to catalyze the conversion of 7α-hydroxycholest-4-en-3-one, a CDCA precursor, to 7α,12α-dihydroxycholest-4-en-3-one, which is an intermediate of CA biosynthesis. In this study we demonstrate that CYP8B1 can also convert CDCA itself to CA. We also show that five derivatives of luciferin are metabolized by CYP8B1 and established a rapid and convenient inhibitor test system. In this way we were able to identify four new CYP8B1 inhibitors, which are aminobenzotriazole, exemestane, ketoconazole and letrozole.
人细胞色素 P450 酶 CYP8B1 是肝脏中胆酸 (CA) 和鹅脱氧胆酸 (CDCA) 平衡的关键调节剂。先前的研究表明，它可以催化 7α-羟胆甾-4-烯-3-酮（CDCA 的前体）转化为 7α,12α-二羟胆甾-4-烯-3-酮，这是 CA 生物合成的中间产物。在这项研究中，我们证明 CYP8B1 也可以将 CDCA 自身转化为 CA。我们还表明，五种荧光素衍生物可被 CYP8B1 代谢，并建立了快速方便的抑制剂测试系统。通过这种方式，我们能够鉴定出四种新的 CYP8B1 抑制剂，分别是氨基苯并三唑、依西美坦、酮康唑和来曲唑。
