RT Journal Article
SR Electronic
T1 Continuum of Host-Gut Microbial Co-metabolism: Host CYP3A4/3A7 Are Responsible for Tertiary Oxidations of Deoxycholate Species
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.118.085670
DO 10.1124/dmd.118.085670
A1 Jian Zhang
A1 Ling-Zhi Gao
A1 Yu-Jie Chen
A1 Ping-Ping Zhu
A1 Shan-Shan Yin
A1 Ming-Ming Su
A1 Yan Ni
A1 Jia Miao
A1 Wen-lin Wu
A1 Hong Chen
A1 Kim L.R. Brouwer
A1 Chang-Xiao Liu
A1 Liang Xu
A1 Wei Jia
A1 Ke Lan
YR 2019
UL http://dmd.aspetjournals.org/content/early/2019/01/03/dmd.118.085670.abstract
AB The gut microbiota modifies endogenous primary bile acids (BAs) to produce exogenous secondary BAs, which may be further metabolized by cytochrome P450 enzymes (CYPs). Our primary aim was to examine how the host adapts to the stress of microbe-derived secondary BAs by CYPs-mediated oxidative modifications on the steroid nucleus. Five unconjugated tri-hydroxyl BAs that were structurally and/or biologically associated with deoxycholate (DCA) were determined in human biological samples by LC-MS/MS in combination with enzyme-digestion techniques. They were identified as DCA-19-ol, DCA-6β-ol, DCA-5β-ol, DCA-6α-ol, DCA-1β-ol and DCA-4β-ol based on matching with in-lab synthesized standards. Metabolic inhibition assays in human liver microsomes and recombinant CYP assays revealed that CYP3A4 and CYP3A7 were responsible for the regioselective oxidations of both DCA and its conjugated forms, glycodeoxycholate (GDCA) and taurodeoxycholate (TDCA). The modification of secondary BAs to tertiary BAs defines a host liver (primary BAs) - gut microbiota (secondary BAs) - host liver (tertiary BAs) axis. The regioselective oxidations of DCA, GDCA and TDCA by CYP3A4 and CYP3A7 may help eliminate host-toxic DCA species. The 19- and 4β-hydroxylation of DCA species demonstrated outstanding CYP3A7 selectivity and may be useful indicators of CYP3A7 activity.