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Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency

Tomalik-Scharte, D. and Maiter, D. and Kirchheiner, J. and Ivison, H. E. and Fuhr, U. and Arlt, Wiebke (2010) Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency. European Journal of Endocrinology, 163 (6). p. 919. ISSN 0804-4643

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URL of Published Version: http://dx.doi.org/10.1530/EJE-10-0764

Identification Number/DOI: doi:10.1530/EJE-10-0764

Objective: Patients with congenital adrenal hyperplasia due to P450 oxidoreductase (POR) deficiency(ORD) present with disordered sex development and glucocorticoid deficiency. This is due to disruption of electron transfer from mutant POR to microsomal cytochrome P450 (CYP) enzymes that play a key role in glucocorticoid and sex steroid synthesis. POR also transfers electrons to all major drugmetabolizing CYP enzymes, including CYP3A4 that inactivates glucocorticoid and oestrogens. However, whether ORD results in impairment of in vivo drug metabolism has never been studied.

Design:We studied an adult patient with ORD due to homozygous POR A287P, the most frequent POR mutation in Caucasians, and her clinically unaffected, heterozygous mother. The patient had received standard dose oestrogen replacement from 17 until 37 years of age when it was stopped after she developed breast cancer.

Methods: Both subjects underwent in vivo cocktail phenotyping comprising the oral administration of caffeine, tolbutamide, omeprazole, dextromethorphan hydrobromide and midazolam to assess the five major drug-metabolizing CYP enzymes. We also performed genotyping for variant CYP alleles known to affect drug metabolism.

Results: Though CYP enzyme genotyping predicted normal or high enzymatic activities in both subjects, in vivo assessment showed subnormal activities of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in the patient and of CYP1A2 and CYP2C9 in her mother.

Conclusions: Our results provide in vivo evidence for an important role of POR in regulating drug metabolism and detoxification. In patients with ORD, in vivo assessment of drug-metabolizing activities with subsequent tailoring of drug therapy and steroid replacement should be considered.

Type of Work:Article
Date:2010 (Publication)
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Clinical and Experimental Medicine
Subjects:RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Institution:University of Birmingham
Copyright Holders:European Society of Endocrinology
ID Code:556
Refereed:YES
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