Cytochrome P450 3A (CYP3A) participates in the metabolism of more than 30% of clinical drugs. The vast intra- and inter-individual variations in CYP3A activity pose great challenges to drug development and personalized medicine. It has been disclosed that human CYP3A4 and CYP3A7 are exclusively responsible for the tertiary oxidations of deoxycholic acid (DCA) and glycodeoxycholic acid (GDCA) regioselectivity at C-1 and C-5 This work aimed to compare the 1- and 5-hydroxylation of DCA and GDCA as potential in vitro CYP3A index reactions in both human liver microsomes and recombinant P450 enzymes. The results demonstrated that the metabolic activity of DCA 1- and 5-hydroxylation was 5-10 times higher than that of GDCA, suggesting that 1-hydroxyglycodeoxycholic acid and 5-hydroxyglycodeoxycholic acid may originate from DCA oxidation followed by conjugation in humans. Metabolic phenotyping data revealed that DCA 1-hydroxylation, DCA 5-hydroxylation, and GDCA 5-hydroxylation were predominantly catalyzed by CYP3A4 (>80%), while GDCA 1-hydroxylation had approximately equal contributions from CYP3A4 (41%) and 3A7 (58%). Robust Pearson correlation was established for the intrinsic clearance of DCA 1- and 5-hydroxylation with midazolam (MDZ) 1'- and 4-hydroxylation in fourteen single donor microsomes. Although DCA 5-hydroxylation exhibited a stronger correlation with MDZ oxidation, DCA 1-hydroxylation exhibited higher reactivity than DCA 5-hydroxylation. It is therefore suggested that DCA 1- and 5-hydroxylations may serve as alternatives to T 6-hydroxylation as in vitro CYP3A index reactions. SIGNIFICANCE STATEMENT: The oxidation of DCA and GDCA is primarily catalyzed by CYP3A4 and CYP3A7. This work compared the 1β- and 5β-hydroxylation of DCA and GDCA as in vitro index reactions to assess CYP3A activities. It was disclosed that the metabolic activity of DCA 1β- and 5β-hydroxylation was 5-10 times higher than that of GDCA. Although DCA 1β-hydroxylation exhibited higher metabolic activity than DCA 5β-hydroxylation, DCA 5β-hydroxylation demonstrated stronger correlation with MDZ oxidation than DCA 1β-hydroxylation in individual liver microsomes.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1124/dmd.123.001513 | DOI Listing |
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!