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

Abstract

ObjectivePatients 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 ofin vivodrug metabolism has never been studied.DesignWe studied an adult patient with ORD due to homozygousPORA287P, the most frequentPORmutation 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.MethodsBoth subjects underwentin vivococktail 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 variantCYPalleles known to affect drug metabolism.ResultsThough CYP enzyme genotyping predicted normal or high enzymatic activities in both subjects,in vivoassessment showed subnormal activities of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in the patient and of CYP1A2 and CYP2C9 in her mother.ConclusionsOur results providein vivoevidence for an important role of POR in regulating drug metabolism and detoxification. In patients with ORD,in vivoassessment of drug-metabolizing activities with subsequent tailoring of drug therapy and steroid replacement should be considered.