Effects of cytochromeb5 on drug oxidation activities of human cytochrome P450 (CYP) 3As: similarity of CYP3A5 with CYP3A4 but not CYP3A7


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Abstract

Effects of cytochrome b5 (b5) 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 b5 in approximately one third of the substrates employed in this study. Such enhancement by b5 was roughly similar to that of CYP3A4, while the activities of CYP3A7 were not enhanced by b5 with any substrates employed. Vmax values for midazolam 1′-hydroxylation and amitriptyline N-demethylation by CYP3A5 were increased about twice by addition of b5, which was also seen with CYP3A4, although the extent of the effects of b5 on S50 (Km) and Hill coefficient differed dependent on substrates used. In contrast, b5 did not alter any of these kinetic parameters of CYP3A7. The effects of b5 on kinetic parameters of CYP3A5 were similar to those of CYP3A4 but not CYP3A7. These results suggest that roles of b5 in drug oxidation activities of CYP3A5 and CYP3A4 are different from those of CYP3A7.

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