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

Abstract

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 drug-metabolizing 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.

Figure 1

P450 oxidoreductase (POR) transfers electrons to all microsomal cytochrome P450 (CYP) enzymes. POR thereby impacts on the function of three major metabolic systems involving microsomal CYP enzymes: steroid synthesis in adrenal glands and gonads, cholesterol synthesis (e.g. in developing bone) and metabolism of steroids, drugs and other xenobiotics, mainly in the liver; drug-metabolizing microsomal CYP enzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4; steroidogenic microsomal CYP enzymes: CYP17A1 (17α-hydroxylase/17,20 lyase), CYP21A2 (21-hydroxylase) and CYP19A1 (aromatase); microsomal CYP enzymes involved in sterol synthesis and metabolism: CYP51A1 (14α-lanosterol demethylase) and SQLE (squalene epoxidase); microsomal CYP enzymes involved in retinoic acid metabolism: CYP26A1, CYP26B1 and CYP26C1.

Figure 2

In vivo low dose cocktail phenotyping for assessment of drug-metabolizing CYP enzyme activities in P450 oxidoreductase deficiency. The results of the cocktail phenotyping in subject 1 (patient, A287P/A287P) and subject 2 (mother, A287P/WT) projected on to the reference range obtained in normal controls, with the boxes representing the 25th to 75th percentile and the whiskers indicating 5th and 95th percentiles respectively. Results are represented as multiples of the median enzyme activity observed in the respective normal reference cohorts (for details, see the Methods section).