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Vol. 27, Issue 9, 999-1004, September 1999
Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa,
Japan (H.Y., M. Nakajima, M. Nakamura, M. Nakajima, T.Y.); Takeda
Chemical Industries, Ltd., Osaka, Japan (S.A.); Daiichi Pure Chemicals
Co., Ibaraki, Japan (N.S.); Department of Physiology and Pharmacology,
University of Queensland, St. Lucia, Queensland, Australia (E.M.J.G.);
Department of Biochemistry and Center in Molecular Toxicology,
Vanderbilt University School of Medicine, Nashville, Tennessee
(F.P.G.); and Osaka Prefectural Institute of Public Health, Osaka,
Japan (T.S.)
Activities of testosterone, nifedipine, and midazolam oxidation by
recombinant cytochrome P-450 (P-450) 3A4 coexpressed with human
NADPH-P-450 reductase (NPR) in bacterial membranes (CYP3A4/NPR membranes) were determined in comparison with those of other
recombinant systems and of human liver microsomes with high contents of
CYP3A4. Growth conditions for Escherichia coli
transformed with the bicistronic construct affected expression levels
of CYP3A4 and NPR; an excess of NPR over P-450 in membrane preparations
enhanced CYP3A4-dependent testosterone
6
-hydroxylation activities of the CYP3A4/NPR
membranes. Cytochrome b5
(b5) and apolipoprotein
b5 further enhanced the testosterone
6-hydroxylation activities of CYP3A4/NPR membranes after addition to
either bacterial membranes or purified enzymes. NPR was observed to
enhance catalytic activity when added to the CYP3A4/NPR membranes,
either in the form of bacterial membranes or as purified NPR (in
combination with cholate and b5). Apparent maximal activities of testosterone 6-hydroxylation in
CYP3A4/NPR membranes were obtained when the molar ratio of
CYP3A4/NPR/b5 was adjusted to 1:2:1 by
mixing membranes containing each protein. Testosterone
6-hydroxylation, nifedipine oxidation, and midazolam 4- and 1'-hydroxylation activities in CYP3A4/NPR membranes plus b5 systems were similar to those measured
with microsomes of insect cells coexpressing CYP3A4 with NPR and/or of
human liver microsomes, based on equivalent CYP3A4 contents. These
results suggest that CYP3A4/NPR membrane systems containing
b5 are very useful models for prediction of
the rates for liver microsomal CYP3A4-dependent drug oxidations.
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