Laboratory of Molecular Pharmacology, Endocrinology, and Nephrology, CHU-Québec Research Centre and the Faculty of Pharmacy, Laval University, Quebec City, Québec, Canada.
Clin Pharmacol Ther. 2013 Oct;94(4):533-43. doi: 10.1038/clpt.2013.122. Epub 2013 Jun 12.
Glucuronidation, catalyzed by uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes, detoxifies cholestatic bile acids (BAs). We aimed to (i) characterize the circulating BA-glucuronide (BA-G) pool composition in humans, (ii) determine how sex and UGT polymorphisms influence this composition, and (iii) analyze the effects of the lipid-lowering drug fenofibrate on the circulating BA-G profile in 300 volunteers and 5 cholestatic patients. Eleven BA-Gs were determined in pre- and postfenofibrate samples. Men exhibited higher BA-G concentrations, and various genotype/BA-G associations were discovered in relevant UGT genes. The chenodeoxycholic acid-3G (CDCA-3G) concentration was associated with the UGT2B7 802C>T polymorphism. Glucuronidation assays confirmed the predominant role of UGT2B7 and UGT1A4 in CDCA-3G formation. Fenofibrate exposure increased the serum levels of five BA-G species, including CDCA-3G, and upregulated expression of UGT1A4, but not UGT2B7, in hepatic cells. This study demonstrated that fenofibrate stimulates BA glucuronidation in humans and thus reduces BA toxicity in the liver.
葡萄糖醛酸化由尿苷 5′-二磷酸葡萄糖醛酸基转移酶 (UGT) 酶催化，可使胆汁酸（BAs）解毒。我们旨在：(i) 描述人类循环 BA 葡萄糖醛酸化物 (BA-G) 池的组成，(ii) 确定性别和 UGT 多态性如何影响该组成，以及 (iii) 分析降脂药物非诺贝特对 300 名志愿者和 5 名胆汁淤积患者循环 BA-G 谱的影响。在非诺贝特治疗前后的样本中测定了 11 种 BA-G。男性的 BA-G 浓度更高，并且在相关的 UGT 基因中发现了各种基因型/BA-G 关联。鹅去氧胆酸-3G (CDCA-3G) 浓度与 UGT2B7 802C>T 多态性相关。葡萄糖醛酸化测定证实 UGT2B7 和 UGT1A4 在 CDCA-3G 形成中起主要作用。非诺贝特暴露增加了五种 BA-G 种类的血清水平，包括 CDCA-3G，并在肝细胞中上调 UGT1A4 的表达，但不上调 UGT2B7。本研究表明，非诺贝特刺激人类 BA 葡萄糖醛酸化，从而降低肝脏中 BA 的毒性。
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