Effects of cytochrome b(5) on drug oxidation activities of human cytochrome P450 (CYP) 3As: similarity of CYP3A5 with CYP3A4 but not CYP3A7.
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.
Yamaori
Satoshi
S
Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University, 060-0812 Sapporo, Japan.
Yamazaki
Hiroshi
H
Suzuki
Akihiro
A
Yamada
Ayako
A
Tani
Hirofumi
H
Kamidate
Tamio
T
Fujita
Ken ichi
Ki
Kamataki
Tetsuya
T
D000759:Adjuvants, Anesthesia / Q000378:metabolism; D000639:Amitriptyline / Q000378:metabolism*; D018712:Analgesics, Non-Narcotic / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D002384:Catalysis; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D015786:Cytochromes b5 / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008874:Midazolam / Q000378:metabolism*; D010084:Oxidation-Reduction; D017386:Sequence Homology, Amino Acid
D000759:Adjuvants, Anesthesia; D018712:Analgesics, Non-Narcotic; D000639:Amitriptyline; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam