title: 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.
  
  
  METHODS
  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.
authors.affiliation: School of Clinical and Experimental Medicine, Centre for Endocrinology, Diabetes and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Dorota
authors.initials: D
authors.lastname: Tomalik-Scharte
authors.forename: Dominique
authors.initials: D
authors.lastname: Maiter
authors.forename: Julia
authors.initials: J
authors.lastname: Kirchheiner
authors.forename: Hannah E
authors.initials: HE
authors.lastname: Ivison
authors.forename: Uwe
authors.initials: U
authors.lastname: Fuhr
authors.forename: Wiebke
authors.initials: W
authors.lastname: Arlt
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D054882:Antley-Bixler Syndrome Phenotype / Q000235:genetics / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D012734:Disorders of Sex Development / Q000235:genetics*; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008875:Middle Aged; D009251:NADPH-Ferrihemoprotein Reductase / Q000172:deficiency*; D013256:Steroids / Q000378:metabolism*
chemical_list: D013256:Steroids; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D009251:NADPH-Ferrihemoprotein Reductase