Effects of cytochrome b5 on drug oxidation activities of human cytochrome P450 (CYP) 3As: similarity of CYP3A5 with CYP3A4 but not CYP3A7

Abstract

Effects of cytochrome b 5 ( b 5) on catalytic activities of human cytochrome P450 (CYP) 3A5, CYP3A4, and CYP3A7 coexpressed with human NADPH-cytochrome P450 reductase in Escherichia coli membranes were investigated using 14 substrates. The activities of CYP3A5 were enhanced by addition of b 5 in approximately one third of the substrates employed in this study. Such enhancement by b 5 was roughly similar to that of CYP3A4, while the activities of CYP3A7 were not enhanced by b 5 with any substrates employed. V max values for midazolam 1′-hydroxylation and amitriptyline N-demethylation by CYP3A5 were increased about twice by addition of b 5, which was also seen with CYP3A4, although the extent of the effects of b 5 on S 50 ( K m ) and Hill coefficient differed dependent on substrates used. In contrast, b 5 did not alter any of these kinetic parameters of CYP3A7. The effects of b 5 on kinetic parameters of CYP3A5 were similar to those of CYP3A4 but not CYP3A7. These results suggest that roles of b 5 in drug oxidation activities of CYP3A5 and CYP3A4 are different from those of CYP3A7.