Journal article
Role of NADPH-Cytochrome P450 Reductase and Cytochrome-b5/NADH-b5 Reductase in Variability of CYP3A Activity in Human Liver Microsomes
Drug metabolism and disposition, Vol.37(1), pp.90-96
01/2009
Handle:
https://hdl.handle.net/2376/112560
PMCID: PMC2610240
PMID: 18838505
Abstract
NADPH-cytochrome P450 reductase (CPR) and cytochrome-
b
5
(
b
5
) together with NADH-
b
5
reductase
(
b
5
R) play important roles in cytochrome P450 3A-mediated
drug metabolism via electron transfer. However, it is not clear whether
variability in expression of these accessory proteins contributes to the known
interindividual variability in CYP3A activity. CPR and
b
5
were measured in human liver microsomes (HLMs) by spectrophotometry and
immunoblotting. HLMs from elderly (≥46 years) male donors (
n
= 11)
averaged 27% (
P
= 0.034) and 41% (
P
= 0.011) lower CPR
levels than young (≤45 years) male donors (
n
= 21) for
spectrophotometric and immunoblot values, respectively. Similarly, HLMs from
elderly male donors averaged 43% (
P
= 0.034) and 47% (
P
=
0.011) lower
b
5
levels than young male donors for
spectrophotometric and immunoblot values, respectively. α-Lipoic acid
and 6-propyl-2-thiouracil were evaluated for selectivity of inhibition of CPR
and
b
5
R activities, respectively, using recombinant
enzymes and HLMs, as well as for effects on CYP3A-mediated triazolam
hydroxylation in HLMs with either NADH or β-NADPH. The results indicate
that both compounds are relatively nonselective inhibitors of CPR and
b
5
R activities. Finally, we used multivariate regression
analysis and showed that variability in CPR or
b
5
expression between HLMs does not contribute significantly to variability in
CYP3A-mediated midazolam hydroxylation. Consequently, while aging is
associated with decreased CPR and
b
5
expression in human
livers, this effect does not contribute to CYP3A variability.
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Details
- Title
- Role of NADPH-Cytochrome P450 Reductase and Cytochrome-b5/NADH-b5 Reductase in Variability of CYP3A Activity in Human Liver Microsomes
- Creators
- Lu Gan - Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts (L.G., L.L.v.M., J.S.H., D.J.G., M.H.C.); and Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin (L.A.T.)Lisa L von Moltke - Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts (L.G., L.L.v.M., J.S.H., D.J.G., M.H.C.); and Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin (L.A.T.)Lauren A Trepanier - Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts (L.G., L.L.v.M., J.S.H., D.J.G., M.H.C.); and Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin (L.A.T.)Jerold S Harmatz - Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts (L.G., L.L.v.M., J.S.H., D.J.G., M.H.C.); and Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin (L.A.T.)David J Greenblatt - Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts (L.G., L.L.v.M., J.S.H., D.J.G., M.H.C.); and Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin (L.A.T.)Michael H Court - Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts (L.G., L.L.v.M., J.S.H., D.J.G., M.H.C.); and Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin (L.A.T.)
- Publication Details
- Drug metabolism and disposition, Vol.37(1), pp.90-96
- Academic Unit
- Veterinary Clinical Sciences, Department of
- Publisher
- American Society for Pharmacology and Experimental Therapeutics
- Identifiers
- 99900547574001842
- Language
- English
- Resource Type
- Journal article