TY - JOUR
T1 - Species differences of bile acid redox metabolism
T2 - Tertiary oxidation of deoxycholate is conserved in preclinical animals
AU - Lin, Qiuhong
AU - Tan, Xianwen
AU - Wang, Wenxia
AU - Zeng, Wushuang
AU - Gui, Lanlan
AU - Su, Mingming
AU - Liu, Changxiao
AU - Jia, Wei
AU - Xu, Liang
AU - Lan, Ke
N1 - Funding Information:
This work was supported partly by the Fundamental Research Funds for the Central Universities and the 111 Project of the National Ministry of Education (B18035). 1Q.-H. L. and X.-W. T. contributed equally to this work. https://doi.org/10.1124/dmd.120.090464. s This article has supplemental material available at dmd.aspetjournals.org.
PY - 2020/6
Y1 - 2020/6
N2 - 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 6b-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.
AB - 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 6b-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.
UR - http://www.scopus.com/inward/record.url?scp=85084936873&partnerID=8YFLogxK
U2 - 10.1124/dmd.120.090464
DO - 10.1124/dmd.120.090464
M3 - Journal article
C2 - 32193215
AN - SCOPUS:85084936873
SN - 0090-9556
VL - 48
SP - 499
EP - 507
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
IS - 6
ER -