Role of human cytochrome P450 1A1, 1A2, 1B1, and 3A4 in the 2-, 4-, and 16[alpha ]-hydroxylation of 17[beta ]-estradiol
Abstract
The steady-state kinetics and specific activity of 2-, 4-, and 16alpha-hydroxylation of 17beta-estradiol (E(2)) were evaluated for human cytochrome P450 (CYP) 1A1, 1A2, 1B1, and 3A4 enzymes, using complementary DNA-expressed CYP isoforms. CYP1A2 showed the highest 2-hydroxylation activity, followed by CYP1A1, 1B1, and 3A4. CYP1B1 had the highest 4-hydroxylation activity, followed by CYP1A2, 1A1, and 3A4. The 16alpha-hydroxylation reaction was catalyzed mainly by CYP1A2 and, to a similar, slightly lower extent, CYP3A4 and 1A1, with a lesser contribution by CYP1B1. The E(2) 2-, 4-, and 16alpha-hydroxylation activities of human liver microsomes were 1.3 +/- 0.3, 0.5 +/- 0.06, and 0.3 +/- 0.05 nmol metabolite/min/nmol P450, respectively. The contribution of CYP1A1 and 1B1 (mainly extrahepatic) to the E(2) hydroxylation reactions, relative to CYP1A2 and 3A4 (predominantly hepatic), may be relevant to understanding the process of hormonal carcinogenesis both in liver and in extrahepatic tissues.
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CYP1A2 is the dominant enzyme catalyzing the 16α-hydroxylation of 17β-estradiol, with CYP3A4, CYP1A1 and CYP1B1 also demonstrating this activity.
“Conversely, CYP1A2 is the dominant enzyme catalyzing the 16α-hydroxylation of 17β-estradiol, with CYP3A4, CYP1A1 and CYP1B1 also demonstrating this activity [317].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [317]
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- Authors
- Badawi, A. F., Cavalieri, E. L., & Rogan, E. G.
- Affiliations
- University of Nebraska Medical Center (US)
- Venue
- Metabolism
- Publisher
- Elsevier BV
- Published
- 2001-09
- Volume
- 50
- Issue
- 9
- Pages
- 1001-1003
- ISSN
- 0026-0495 (ISSN-L)
- OpenAlex
- W2087962059
- Cited by
- 184
- References
- 15
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 7 · 2023: 5 · 2022: 11 · 2021: 9 · 2020: 9 · 2019: 8 · 2018: 3 · 2017: 6 · 2016: 5 · 2015: 6 · 2014: 9 · 2013: 9 · 2012: 8
- FWCI
- 5.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ca049917-11)
- National Cancer Institute (P01CA049210, R01CA49917, P01CA 49210, CA-36727, P30CA036727)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Keywords
- estradiol, cytochrome P450, CYP1A2, CYP1A1, CYP1B1, CYP3A4, 2-hydroxylation, 4-hydroxylation, 16α-hydroxylation, estradiol metabolism, steady-state kinetics, liver microsomes, extrahepatic metabolism, hormonal carcinogenesis
- MeSH terms
- Aryl Hydrocarbon Hydroxylases, Cytochrome P-450 Enzyme System, Estradiol, Humans, Mixed Function Oxygenases, Hydroxylation, Isoenzymes, Kinetics, Microsomes, Liver, Recombinant Proteins, Cytochrome P-450 CYP1A1, Cytochrome P-450 CYP1A2, Steroid 16-alpha-Hydroxylase, Cytochrome P-450 CYP3A, Cytochrome P-450 CYP1B1, Cytochrome P-450 CYP2C8, Cytochrome P-450 CYP2C9
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