ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2006) 12 S14

P450 oxidoreductase and androgen metabolism

Vivek Dhir, Nils Krone, Hannah E Ivison, Paul M Stewart, Cedric HL Shackleton & Wiebke Arlt

Division of Medical Sciences, University of Birmingham, Birmingham, United Kingdom.

P450 oxidoreductase (POR) has a pivotal role as electron donor to all cytochrome P450 enzymes that are microsomally located, i.e. CYP type II enzymes. Importantly, those include key enzymes involved in glucocorticoid and sex steroid biosynthesis such as CYP17 and CYP21. In addition, the activity of hepatic CYP enzymes involved in drug metabolism and detoxification also crucially depend on the transfer of electrons from NADPH via POR. Recently, mutations in P450 oxidoreductase have been identified as disease-causing in patients with congenital adrenal hyperplasia (CAH) with apparent combined CYP17 and CYP21 deficiency. Most identified mutations are located in close proximity to the binding domains of NADPH, FAD or FMN of the POR molecule, thereby disrupting electron transfer. CAH due to P450 oxidoreductase deficiency (ORD) has a broad phenotypic spectrum with two unique features. Firstly, affected patients may present with skeletal malformations and, secondly, ambiguous genitalia are observed in both sexes. Disruption of CYP17 activity in the context of ORD results in decreased production of DHEA and subsequently of sex steroids, which readily explains undervirilisation in affected boys. However, this does not explain the apparently contradictory finding of virilised genitalia in girls while circulating androgens are concurrently low. This may be explained by the presence of an alternative pathway towards androgen synthesis in human fetal life, which does not require DHEA biosynthesis but still yields active androgen. Analysis of urinary steroid excretion in neonates affected by ORD supports this hypothesis. Furthermore, detailed genotype-phenotype analysis reveals that POR mutations similarly knock down the activity of the conventional androgen pathway via DHEA. However, specific mutations differentially affect the alternative pathway thereby defining the genital phenotype of affected children. Taken together, ORD provides novel insights into the exact mechanisms underlying electron transfer via POR and strikingly highlights the significance of redox regulation for steroidogenesis.

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