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Substrate-specific modulation of CYP3A4 activity by genetic variants of cytochrome P450 oxidoreductase

Title
Substrate-specific modulation of CYP3A4 activity by genetic variants of cytochrome P450 oxidoreductase
Authors
Agrawal V.Choi J.H.Giacomini K.M.Miller W.L.
Ewha Authors
최지하
SCOPUS Author ID
최지하scopus
Issue Date
2010
Journal Title
Pharmacogenetics and Genomics
ISSN
1744-6872JCR Link
Citation
vol. 20, no. 10, pp. 611 - 618
Indexed
SCI; SCIE; SCOPUS scopus
Abstract
OBJECTIVES: CYP3A4 receives electrons from P450 oxidoreductase (POR) to metabolize about 50% of clinically used drugs. There is substantial inter-individual variation in CYP3A4 catalytic activity that is not explained by CYP3A4 genetic variants. CYP3A4 is flexible and distensible, permitting it to accommodate substrates varying in shape and size. To elucidate the mechanisms of variability in CYP3A4 catalysis, we examined the effects of genetic variants of POR, and explored the possibility that substrate-induced conformational changes in CYP3A4 differentially affect the ability of POR variants to support catalysis. METHODS: We expressed human CYP3A4 and four POR variants (Q153R, A287P, R457H, A503V) in bacteria, reconstituted them in vitro and measured the Michaelis constant and maximum velocity with testosterone, midazolam, quinidine and erythromycin as substrates. RESULTS: POR A287P and R457H had low activity with all substrates; Q153R had 76-94% of wild-type (WT) activity with midazolam and erythromycin, but 129-150% activity with testosterone and quinidine. The A503V polymorphism reduced the CYP3A4 activity to 61-77% of WT with testosterone and midazolam, but had nearly WT activity with quinidine and erythromycin. CONCLUSION: POR variants affect CYP3A4 activities. The impact of a POR variant on catalysis by CYP3A4 is substrate-specific, probably because of substrate-induced conformational changes in CYP3A4. © 2010 Wolters Kluwer Health

Lippincott Williams & Wilkins.
DOI
10.1097/FPC.0b013e32833e0cb5
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의학전문대학원 > 의학과 > Journal papers
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