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1. Pharmacogenet Genomics. 2012 Apr 26. [Epub ahead of print]

Effect of P450 oxidoreductase variants on the metabolism of model substrates
mediated by CYP2C9.1, CYP2C9.2, and CYP2C9.3.

Subramanian M, Agrawal V, Sandee D, Tam HK, Miller WL, Tracy TS.

aDepartment of Experimental and Clinical Pharmacology, College of Pharmacy,
University of Minnesota, Minneapolis, Minnesota bDepartment of Pediatrics,
University of California San Francisco, San Francisco, California, USA.

OBJECTIVES: CYP2C9 is a microsomal cytochrome P450 that receives electrons from
P450 oxidoreductase (POR) to metabolize about 15% of clinically used drugs.
Similar to many P450 enzymes, CYP2C9 is polymorphic, with the hypomorphic *2 and
*3 variants accounting for about 20% of White alleles. POR is also polymorphic,
with the amino acid sequence variant A503V accounting for 19-37% of alleles in
different populations. We aimed to understand how polymorphisms in these two
interacting proteins might affect drug metabolism. METHODS: We assayed the
activities of CYP2C9.1, CYP2C9.2, and CYP2C9.3 to metabolize diclofenac,
flurbiprofen, and tolbutamide using a wild type or one of four POR variants
(Q153R, A287P, R457H, and A503V). Human CYP2C9 and POR variants were expressed in
bacteria, purified, and reconstituted in vitro and the Michaelis constant and
maximum velocity were measured with each CYP2C9/POR combination and each
substrate. RESULTS: With wild-type POR, the CYP2C9 activities were
CYP2C9.1>CYP2C9.2>>CYP2C9.3 with all three substrates. Both the common A503V
polymorphism and the rare Q153R variant showed modest increases in activity with
all three CYP2C9 isoforms and all three substrates. This is in contrast to
previous studies in which A503V showed a modest loss of function with CYP1A2,
CYP2C19, CYP2D6, CYP3A4, and CYP17A1. The disease-causing POR variants A287P and
R457H had a very low or unmeasurable activity with all CYP2C9 isoforms and all
substrates, which is consistent with their low activities with other CYPs.
CONCLUSION: POR variants affect CYP2C9 activities. The impact of a POR variant on
catalysis varies with the isoform of CYP2C9 and the assay substrate.

PMID: 22547083 [PubMed - as supplied by publisher]