Extraadrenal steroid 21-hydroxylation is not mediated by P450c21.
Open accessAbstract
The 21-hydroxylation of progesterone to deoxycorticosterone (DOC) and of 17-hydroxyprogesterone to 11-deoxycortisol in the human adrenal cortex is mediated by a single enzyme termed P450c21. Extraadrenal tissues can clear circulating progesterone and progesterone sulfate by 21-hydroxylation to DOC and DOC-sulfate. It has previously been established that such extraadrenal 21-hydroxylase activity is widely distributed in adult and fetal tissues, but it has not been known if extra-adrenal 21-hydroxylation is mediated by the same P450c21 enzyme found in the adrenal. We examined human RNA from fetal adrenal, liver, kidney, lung, brain, heart, skin, spleen, testis, and placenta by solution hybridization to human P450c21 probes transcribed from cloned human P450c21 cDNA, followed by nuclease protection and acrylamide gel electrophoresis. No P450c21 mRNA was detectable in any extraadrenal tissue. The sensitivity of the assay would have detected P450c21 mRNA at 0.01% of its abundance in the human fetal adrenal. Similar experiments in rats showed no P450c21 mRNA in brain, heart, kidney, liver, lung, testis, ovary, or uterus. These results clearly demonstrate that one or more enzymes other than the classical adrenal 21-hydroxylase are responsible for human and rat extraadrenal 21-hydroxylation.
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Extraadrenal 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 [366]
The brain also 21-hydroxylates steroids, leading to the synthesis of DOC and its 3α,5α-reduced product, tetrahydro-DOC, which acts similarly to Allo at GABA A receptors; however, the brain does not express significant amounts of P450c21.
“The brain also 21-hydroxylates steroids (702), leading to the synthesis of DOC and its 3␣,5␣-reduced product, tetrahydro-DOC, which acts similarly to Allo at GABA A receptors (703); however, the brain does not express significant amounts of P450c21 (366).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [366]
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- Authors
- Mellon, S. H., & Miller, W. L.
- Affiliations
- University of California, San Francisco (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1989-11-01
- Volume
- 84
- Issue
- 5
- Pages
- 1497-1502
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC304014
- OpenAlex
- W2042387650
- Semantic Scholar
- 05a4d1a221c0d2f8494792cd81e6a2d9a68a6e19
- Cited by
- 121
- References
- 24
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2018: 1 · 2016: 2 · 2015: 4 · 2014: 1 · 2013: 1 · 2012: 2
- FWCI
- 5.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- W. M. Keck Foundation
- March of Dimes Foundation
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-37922)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 22013)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Keywords
- P450c21, 21-hydroxylase, deoxycorticosterone, 11-deoxycortisol, progesterone, 17-hydroxyprogesterone, tissue distribution, adrenal cortex, fetal adrenal
- MeSH terms
- Adrenal Glands, Animals, Cloning, Molecular, DNA, Fetus, Humans, Hydroxyprogesterones, Nucleic Acid Hybridization, Progesterone, RNA, Messenger, Steroid Hydroxylases, Steroid 21-Hydroxylase, Tissue Distribution, RNA Probes, 17-alpha-Hydroxyprogesterone, Rats
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