Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency
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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.
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Arterial hypertension has been documented in homozygous carriers of p.A287P, probably caused by excess deoxycorticosterone production as in classical 17α-hydroxylase deficiency.
“We previously demonstrated predominant 17α-hydroxylase over 21-hydroxylase impairment by p.A287P (21), and indeed, arterial hypertension has been documented in homozygous carriers (3, 12), probably caused by excess deoxycorticosterone production as in classical 17α-hydroxylase deficiency.”
From Genotype-Phenotype Analysis in Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency (2012) · cites this paper as [12]
The Results identify a homozygous p.A287P patient, and Subjects and methods reports repeatedly elevated blood pressure. The Discussion calls this manifest arterial hypertension, most likely due to mild mineralocorticoid excess. It does not identify excess deoxycorticosterone production or make the comparison with classical 17α-hydroxylase deficiency. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMineralocorticoid excess and consequent hypertension are uncommon in the overall PORD population, but several studies report a higher incidence of hypertension among carriers of the p.A287P variant.
“Although mineralocorticoid excess and consequent hypertension are uncommon in the overall PORD population, several studies have reported a higher incidence of hypertension among carriers of the p.A287P variant (63, 64).”
From Case Report: Integrating clinical presentation and genetic analysis in P450 oxidoreductase deficiency: a novel mutation and systematic review (2026) · cites this paper as [64]
The Discussion reports hypertension in one patient with homozygous p.A287P, most likely due to mild mineralocorticoid excess. It does not establish that hypertension is uncommon across the overall PORD population or that its incidence is higher among p.A287P carriers. Page numbers are not available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn vivo impairment, particularly of CYP3A4, has been demonstrated in a patient with PORD.
“In vivo impairment, particularly of CYP3A4, has recently been demonstrated in a patient with PORD (12), which has important implications for steroid replacement and drug therapy in affected patients.”
From Genotype-Phenotype Analysis in Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency (2012) · cites this paper as [12]
PORD results in decreased hepatic drug metabolism, due to reduced capacity of CYP3A4, but also CYP1A2, CYP2D6, CYP2C9, and CYP2C19.
“PORD also results in decreased hepatic drug metabolism, due to reduced capacity of CYP3A4, but also CYP1A2, CYP2D6, CYP2C9, and CYP2C19 (46).”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [46]
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- Authors
- Tomalik-Scharte, D., Maiter, D., Kirchheiner, J., Ivison, H. E., Fuhr, U., & Arlt, W.
- Affiliations
- Cliniques Universitaires Saint-Luc (BE)
- Universität Ulm (DE)
- University of Birmingham (GB)
- University of Cologne (DE)
- Corresponding author
- Arlt, Wiebke
- Venue
- European Journal of Endocrinology
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-12
- Volume
- 163
- Issue
- 6
- Pages
- 919-924
- ISSN
- 0804-4643 (ISSN-L)
- 1479-683X
- PMC
- PMC2977993
- OpenAlex
- W2101613203
- Cited by
- 77
- References
- 33
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 3 · 2023: 6 · 2022: 2 · 2021: 4 · 2020: 5 · 2019: 4 · 2018: 5 · 2017: 4 · 2016: 5 · 2015: 8 · 2014: 5 · 2013: 6 · 2012: 4
- FWCI
- 5.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- University of Birmingham Institutional Research Archive (University of Birmingham) (acceptedVersion)
- Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion, other-oa)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Medical Research Council (0900567)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- congenital adrenal hyperplasia, P450 oxidoreductase deficiency, drug metabolism, CYP3A4, CYP1A2, CYP2C9, CYP2D6, CYP1B1, glucocorticoid metabolism, sex steroid synthesis, estrogen replacement therapy, breast cancer
- MeSH terms
- Adrenal Hyperplasia, Congenital, Adult, Aged, Aryl Hydrocarbon Hydroxylases, Cytochrome P-450 Enzyme System, Female, Humans, Liver, Middle Aged, NADPH-Ferrihemoprotein Reductase, Disorders of Sex Development, Steroids, Cytochrome P-450 CYP1A2, Antley-Bixler Syndrome Phenotype, Cytochrome P-450 CYP2C9
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