The DOI matches its Crossref record; 88 of the 88 references it cites were found in a registry or an index.
Regioselective hydroxylation of steroid hormones by human cytochromes P450
Abstract
This article reviews in vitro metabolic activities [including Michaelis constants (Km), maximal velocities (Vmax) and Vmax/Km] and drug-steroid interactions [such as induction and cooperativity (activation)] of cytochromes P450 (P450 or CYP) in human tissues, including liver and adrenal gland, for 14 kinds of endogenous steroid compounds, including allopregnanolone, cholesterol, cortisol, cortisone, dehydroepiandrosterone, estradiol, estrone, pregnenolone, progesterone, testosterone and bile acids (cholic acid). First, we considered the drug-metabolizing P450s. 6β-Hydroxylation of many steroids, including cortisol, cortisone, progesterone and testosterone, was catalyzed primarily by CYP3A4. CYP1A2 and CYP3A4, respectively, are likely the major hepatic enzymes responsible for 2-/4-hydroxylation and 16α-hydroxylation of estradiol and estrone, steroids that can contribute to breast cancer risk. In contrast, CYP1A1 and CYP1B1 predominantly metabolized estrone and estradiol to 2- and 4-catechol estrogens, which are endogenous ultimate carcinogens if formed in the breast. Some metabolic activities of CYP3A4, including dehydroepiandrosterone 7β-/16α-hydroxylation, estrone 2-hydroxylation and testosterone 6β-hydroxylation, were higher than those for polymorphically expressed CYP3A5. Next, we considered typical steroidogenic P450s. CYP17A1, CYP19A1 and CYP27A1 catalyzed steroid synthesis, including hydroxylation at 17α, 19 and 27 positions, respectively. However, it was difficult to predict which hepatic drug-metabolizing P450 or steroidogenic P450 will be mainly responsible for metabolizing each steroid hormone in vivo based on these results. Further research is required on the metabolism of steroid hormones by various P450s and on prediction of their relative contributions to in vivo metabolism. The findings collected here provide fundamental and useful information on the metabolism of steroid compounds.
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In the citing paper
“Hepatic xenobiotic-metabolizing members of the CYP superfamily are able to modify steroid hormones and generate a plethora of minor steroid metabolites [116].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [116]
In the citing paper
“with at least 17 hepatic CYPs potentially participating in the metabolism of steroids [[116], [117], [118]].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [116]
In the citing paper
“CYP3A4 is the most abundant P450 in the liver (∼30%) (Shimada et al., 1994) and predominantly, though not exclusively, catalyses the 6β-hydroxylation of T and the 16α- and 7α-hydroxylation of DHEA (Niwa et al., 2015).”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Niwa et al., 2015
In the citing paper
“Prostate cells also express CYP3A4 that can inactivate T by conversion to mainly 6βOH-T (with 2β-, 15α/β- and 11β-hydroxyl side product formation (Niwa et al., 2015))”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Niwa et al., 2015
Citations
Cites
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Summary of information on human CYP enzymes: human P450 metabolism data
Rendić, S. (2002) · Drug Metabolism Reviews · doi:10.1081/dmr-120001392 · Cited by 819
Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer
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Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7
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Cited by
Sorted by citations
Schiffer, L., Barnard, L., Baranowski, E. S., Gilligan, L. C., Taylor, A. E., Arlt, W., Shackleton, C. H. L., & Storbeck, K.-H. (2019) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2019.105439 · Cited by 450
“2, hepatic xenobiotic-metabolizing members of the CYP superfamily are able to modify steroid hormones and generate a plethora of minor steroid metabolites [116].”
Sex‐specificity in lung cancer risk
Stapelfeld, C., Dammann, C., & Maser, E. (2019) · International Journal of Cancer · doi:10.1002/ijc.32716 · Cited by 225
Intracrine androgen biosynthesis, metabolism and action revisited
Schiffer, L., Arlt, W., & Storbeck, K.-H. (2018) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.08.016 · Cited by 217
“Prostate cells also express CYP3A4 that can inactivate T by conversion to mainly 6bOH-T (with 2b-, 15a/b- and 11b-hydroxyl side product formation (Niwa et al., 2015)) and a decrease of CYP3A4 expression is observed in prostate cancer (Fujimura et al.”
Arzuaga, X., Smith, M. T., Gibbons, C. F., Skakkebæk, N. E., Yost, E. E., Beverly, B., Hotchkiss, A. K., Hauser, R. B., de Souza, R. P., Schrader, S. M., et al. (2019) · Environmental Health Perspectives · doi:10.1289/ehp5045 · Cited by 90
Liver and Steroid Hormones—Can a Touch of p53 Make a Difference?
Charni‐Natan, M., Aloni-Grinstein, R., Osher, E., & Rotter, V. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00374 · Cited by 91
Metadata
- Authors
- Niwa, T., Murayama, N., Imagawa, Y., & Yamazaki, H.
- Affiliations
- Shujitsu University (JP)
- Showa Pharmaceutical University (JP)
- Corresponding author
- Yamazaki, Hiroshi
- Venue
- Drug Metabolism Reviews
- Publisher
- Informa UK Limited
- Published
- 2015-02-13
- Volume
- 47
- Issue
- 2
- Pages
- 89-110
- ISSN
- 0360-2532 (ISSN-L)
- 1097-9883
- OpenAlex
- W2041685866
- Cited by
- 121
- References
- 88
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 7 · 2023: 12 · 2022: 18 · 2021: 10 · 2020: 13 · 2019: 14 · 2018: 5 · 2017: 10 · 2016: 10 · 2015: 2
- FWCI
- 1.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drug Metabolism Reviews (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Physical Sciences › Chemistry › Organic Chemistry › Steroid Chemistry and Biochemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Keywords
- steroid hormone metabolism, cytochrome P450, regioselective hydroxylation, CYP3A4, CYP1A2, CYP1A1, CYP1B1, CYP17A1, CYP19A1, CYP27A1, CYP3A5, enzyme induction, cooperativity, estradiol, estrone, catechol estrogens, breast cancer risk, steroidogenesis, adrenal gland, liver
- MeSH terms
- Adrenal Glands, Cholesterol, Cytochrome P-450 Enzyme System, Estradiol, Humans, Hydroxylation, Liver, Testosterone, In Vitro Techniques
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