Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, China (Q.L., X.T., W.W., W.Z., L.G., L.X., K.L.); Metabolomics Shared Resource, University of Hawaii Cancer Center, Honolulu, HI, (M.S., W.J.); State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China (C.L.); and Chengdu Health-Balance Medical Technology Co., Ltd., Chengdu, China (Q.L., X.T., W.W., W.Z., L.G., K.L.).
Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, China (Q.L., X.T., W.W., W.Z., L.G., L.X., K.L.); Metabolomics Shared Resource, University of Hawaii Cancer Center, Honolulu, HI, (M.S., W.J.); State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China (C.L.); and Chengdu Health-Balance Medical Technology Co., Ltd., Chengdu, China (Q.L., X.T., W.W., W.Z., L.G., K.L.)
Drug Metab Dispos. 2020 Jun;48(6):499-507. doi: 10.1124/dmd.120.090464. Epub 2020 Mar 19.
It was recently disclosed that CYP3A is responsible for the tertiary stereoselective oxidations of deoxycholic acid (DCA), which becomes a continuum mechanism of the host-gut microbial cometabolism of bile acids (BAs) in humans. This work aims to investigate the species differences of BA redox metabolism and clarify whether the tertiary metabolism of DCA is a conserved pathway in preclinical animals. With quantitative determination of the total unconjugated BAs in urine and fecal samples of humans, dogs, rats, and mice, it was confirmed that the tertiary oxidized metabolites of DCA were found in all tested animals, whereas DCA and its oxidized metabolites disappeared in germ-free mice. The in vitro metabolism data of DCA and the other unconjugated BAs in liver microsomes of humans, monkeys, dogs, rats, and mice showed consistencies with the BA-profiling data, confirming that the tertiary oxidation of DCA is a conserved pathway. In liver microsomes of all tested animals, however, the oxidation activities toward DCA were far below the murine-specific 6-oxidation activities toward chenodeoxycholic acid (CDCA), ursodeoxycholic acid, and lithocholic acid (LCA), and 7-oxidation activities toward murideoxycholic acid and hyodeoxycholic acid came from the 6-hydroxylation of LCA. These findings provided further explanations for why murine animals have significantly enhanced downstream metabolism of CDCA compared with humans. In conclusion, the species differences of BA redox metabolism disclosed in this work will be useful for the interspecies extrapolation of BA biology and toxicology in translational researches. SIGNIFICANCE STATEMENT: It is important to understand the species differences of bile acid metabolism when deciphering biological and hepatotoxicology findings from preclinical studies. However, the species differences of tertiary bile acids are poorly understood compared with primary and secondary bile acids. This work confirms that the tertiary oxidation of deoxycholic acid is conserved among preclinical animals and provides deeper understanding of how and why the downstream metabolism of chenodeoxycholic acid dominates that of cholic acid in murine animals compared with humans.
最近披露，CYP3A 负责脱氧胆酸（DCA）的三级立体选择性氧化，这成为人类胆汁酸（BAs）的宿主-肠道微生物共代谢的连续机制。本研究旨在探讨 BA 氧化代谢的种属差异，并阐明 DCA 的三级代谢是否是临床前动物的保守途径。通过对人体、犬、大鼠和小鼠尿液和粪便样品中总未结合 BAs 的定量测定，证实所有检测动物均发现 DCA 的三级氧化代谢物，而无菌小鼠中 DCA 及其氧化代谢物消失。DCA 和其他未结合 BAs 在人、猴、犬、大鼠和小鼠肝微粒体中的体外代谢数据与 BA 分析数据一致，证实 DCA 的三级氧化是一种保守途径。然而，在所有检测动物的肝微粒体中，DCA 的氧化活性远低于鼠类特异性 6-氧化对鹅脱氧胆酸（CDCA）、熊脱氧胆酸和石胆酸（LCA）的活性，7-氧化对鼠脱氧胆酸和去氧胆酸的活性来自 LCA 的 6-羟化。这些发现进一步解释了为什么与人类相比，鼠类动物对 CDCA 的下游代谢有显著增强。总之，本研究揭示的 BA 氧化代谢的种属差异将有助于在转化研究中对 BA 生物学和毒理学进行种间外推。 意义陈述：在解读临床前研究中的生物学和肝毒性发现时，了解胆汁酸代谢的种属差异很重要。然而，与初级和次级胆汁酸相比，三级胆汁酸的种属差异了解甚少。本研究证实，脱氧胆酸的三级氧化在临床前动物中是保守的，并深入了解了为什么与人类相比，鼠类动物中 CDCA 的下游代谢占主导地位，而胆酸的下游代谢则占主导地位。
