Reduction in hepatic drug metabolizing CYP3A4 activities caused by P450 oxidoreductase mutations identified in patients with disordered steroid metabolism

Flück, Christa E; Mullis, Primus E; Pandey, Amit V (2010). Reduction in hepatic drug metabolizing CYP3A4 activities caused by P450 oxidoreductase mutations identified in patients with disordered steroid metabolism. Biochemical and biophysical research communications, 401(1), pp. 149-53. Orlando, Fla.: Academic Press 10.1016/j.bbrc.2010.09.035

Full text not available from this repository. (Request a copy)

Cytochrome P450 3A4 (CYP3A4), the major P450 present in human liver metabolizes approximately half the drugs in clinical use and requires electrons supplied from NADPH through NADPH-P450 reductase (POR, CPR). Mutations in human POR cause a rare form of congenital adrenal hyperplasia from diminished activities of steroid metabolizing P450s. In this study we examined the effect of mutations in POR on CYP3A4 activity. We used purified preparations of wild type and mutant human POR and in vitro reconstitution with purified CYP3A4 to perform kinetic studies. We are reporting that mutations in POR identified in patients with disordered steroidogenesis/Antley-Bixler syndrome (ABS) may reduce CYP3A4 activity, potentially affecting drug metabolism in individuals carrying mutant POR alleles. POR mutants Y181D, A457H, Y459H, V492E and R616X had more than 99% loss of CYP3A4 activity, while POR mutations A287P, C569Y and V608F lost 60-85% activity. Loss of CYP3A4 activity may result in increased risk of drug toxicities and adverse drug reactions in patients with POR mutations.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine

UniBE Contributor:

Flück, Christa; Mullis, Primus-Eugen and Pandey, Amit Vikram

ISSN:

0006-291X

Publisher:

Academic Press

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:13

Last Modified:

06 Dec 2013 13:22

Publisher DOI:

10.1016/j.bbrc.2010.09.035

PubMed ID:

20849814

Web of Science ID:

000283204100026

URI:

https://boris.unibe.ch/id/eprint/2813 (FactScience: 205727)

Actions (login required)

Edit item Edit item
Provide Feedback