Extraadrenal 21-Hydroxylation by CYP2C19 and CYP3A4: Effect on 21-Hydroxylase Deficiency
Open accessAbstract
CONTEXT: 21-Hydroxylase deficiency (21OHD) is caused by CYP21A2 gene mutations disrupting the adrenal 21-hydroxylase, P450c21. CYP21A2 mutations generally correlate well with the 21OHD phenotype, but some children with severe CYP21A2 mutations have residual 21-hydroxylase activity. Some hepatic P450 enzymes can 21-hydroxylate progesterone, but their physiological relevance in modifying 21OHD is not known. OBJECTIVE: We determined the ability of CYP2C19 and CYP3A4 to 21-hydroxylate progesterone and 17-hydroxyprogesterone (17OHP), determined the impact of the common P450 oxidoreductase (POR) variant A503V on these activities, and examined correlations between CYP2C19 variants and phenotype in patients with 21OHD. METHODS: Bacterially expressed, N-terminally modified, C-His-tagged human P450c21, CYP2C19, and CYP3A4 were combined with bacterially expressed wild-type and A503V POR. The 21-hydroxylation of radiolabeled progesterone and 17OHP was assessed, and the Michaelis constant (Km) and maximum velocity (Vmax) of the reactions were measured. CYP2C19 was genotyped in 21OHD patients with genotypes predicting severe congenital adrenal hyperplasia. RESULTS: Compared to P450c21, the Vmax/Km for 21-hydroxylation of progesterone by CYP2C19 and CYP3A4 were 17 and 10%, respectively. With both forms of POR, the Km for P450c21 was approximately 2.6 microm, the Km for CYP2C19 was approximately 11 microm, and the Km for CYP3A4 was approximately 110 microm. Neither CYP2C19 nor CYP3A4 could 21-hydroxylate 17OHP. The CYP2C19 ultrametabolizer allele CYP2C19 17 was homozygous in one of five patients with a 21OHD phenotype that was milder than predicted by the CYP21A2 genotype. CONCLUSIONS: CYP2C19 and CYP3A4 can 21-hydroxylate progesterone but not 17OHP, possibly ameliorating mineralocorticoid deficiency, but not glucocorticoid deficiency. Multiple enzymes probably contribute to extraadrenal 21-hydroxylation.
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The fetus with CAH is only virilized by its own adrenal androgens; even when maternal testosterone concentrations reach 300 ng/dl in a mother who herself has CAH, the female fetus is not virilized because placental aromatase inactivates the androgens from the maternal circulation.
“The fetus with CAH fetus is only virilized by its own adrenal androgens; even when maternal testosterone concentrations reach 300 ng/dl in a mother who herself has CAH, the female fetus is not virilized because placental aromatase inactivates the androgens from the maternal circulation (101).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [101]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredExtraadrenal 21-hydroxylation is not mediated by the P450c21 enzyme found in the adrenal, but it appears to be catalyzed by CYP2C9, CYP3A4, CYP2C19, and possibly other enzymes as well.
“However, extraadrenal 21-hydroxylation is not mediated by the P450c21 enzyme found in the adrenal (366), but it appears to be catalyzed by CYP2C9, CYP3A4, CYP2C19, and possibly other enzymes as well (367, 368).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [368]
The Discussion reports that CYP2C19 and CYP3A4 21-hydroxylate progesterone in vitro and proposes that additional enzymes may contribute. Our copy does not establish CYP2C9 as one of those enzymes; it also reports that CYP2C19 and CYP3A4 did not 21-hydroxylate 17OHP. The separate assertion about P450c21 is attached to citation 366, not this source. (LLM, conf=0.87)
Experimental — accuracy not yet measuredHuman hepatic CYP2C19 and CYP3A4 can 21-hydroxylate progesterone but not 17OHP and thus may account, in part, for the diminished mineralocorticoid requirements in adult patients.
“Human hepatic CYP2C19 and CYP3A4 can 21hydroxylate progesterone but not 17OHP and thus may account, in part, for the diminished mineralocorticoid requirements in adult patients (368).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [368]
Placental aromatase activity protects the fetus from maternal androgens.
“Placental aromatase activity protects the fetus from maternal androgens (101).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [101]
The Discussion addresses extraadrenal 21-hydroxylation of progesterone and its possible effect on congenital adrenal hyperplasia, not placental aromatase. Searches for placental aromatase and protection from maternal androgens found no passage in our copy addressing the claim. (LLM, conf=0.73)
Experimental — accuracy not yet measuredApart from CAH genes, other genes may modify steroid action, salt balance or androgen sensitivity and affect phenotype.
“Apart from CAH genes, other genes may modify steroid action, salt balance or androgen sensitivity and affect phenotype.136,137,138”
From Congenital adrenal hyperplasia (2017) · cites this paper as [136]
CYP2C19 and CYP3A4 can 21-hydroxylate progesterone and pregnenolone.
“CYP2C19 and CYP3A4 can 21-hydroxylate progesterone and pregnenolone”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [140]
CYP2C19 and CYP3A4 are not capable of catalyzing the 21-hydroxylation of 17OHP to 11-deoxycortisol.
“the two enzymes are not capable of catalyzing the 21-hydroxylation of 17OHP to 11-deoxycortisol [140].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [140]
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Self-citation
- Authors
- Gomes, L. G., Huang, N., Agrawal, V., Mendonça, B. B., Bachega, T. A. S. S., & Miller, W. L.
- Affiliations
- Universidade de São Paulo (BR)
- University of California, San Francisco (US)
- Department of Endocrinology-LIM42 (L.G.G., B.B.M., T.A.S.S.B.), Hospital das Clinicas da Universidade de São Paulo, 05403-900 São Paulo, Brazil
- Corresponding author
- Miller, Walter L.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2009-01-01
- Volume
- 94
- Issue
- 1
- Pages
- 89-95
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC2630875
- OpenAlex
- W2171084347
- Semantic Scholar
- abdbca9de9b3d44f29ca77942752c384330a353f
- Cited by
- 91
- References
- 44
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 2 · 2022: 5 · 2021: 6 · 2020: 4 · 2019: 5 · 2018: 3 · 2017: 4 · 2016: 6 · 2015: 10 · 2014: 6 · 2013: 5 · 2012: 2
- FWCI
- 3.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
- Scientific Electronic Library Online (São Paulo Research Foundation, Latin American and Caribbean Center on Health Sciences Information, Conselho Nacional de Desenvolvimento Científico e Tecnológico) (publishedVersion)
- Funders
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- National Institutes of Health
- University of California, San Francisco
- National Institute of General Medical Sciences (R01GM073020)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- congenital adrenal hyperplasia, CYP2C19, CYP3A4, 17-hydroxyprogesterone, P450c21, CYP2C19*17
- MeSH terms
- Adrenal Hyperplasia, Congenital, Aryl Hydrocarbon Hydroxylases, Child, Child, Preschool, Female, Humans, Hydroxylation, Male, Progesterone, 17-alpha-Hydroxyprogesterone, Cytochrome P-450 CYP3A, Cytochrome P-450 CYP2C19
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