Regioselective hydroxylation of steroid hormones by human cytochromes P450

Niwa, Toshiro; Murayama, Norie; Imagawa, Yurie; Yamazaki, Hiroshi

doi:10.3109/03602532.2015.1011658

Cited by 121Pharmacogenetics and Drug MetabolismSteroid Chemistry and BiochemistryEstrogen and related hormone effects

Regioselective hydroxylation of steroid hormones by human cytochromes P450

Niwa, Toshiro, Murayama, Norie, Imagawa, Yurie, Yamazaki, Hiroshi·2015·Drug Metabolism Reviews

DOI 10.3109/03602532.2015.1011658

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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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Hepatic xenobiotic-metabolizing CYPs are able to modify steroid hormones and generate a plethora of minor steroid metabolites.
“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]
At least 17 hepatic CYPs potentially participate in the metabolism of steroids.
“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]
CYP3A4 is the most abundant P450 in the liver and predominantly, though not exclusively, catalyses the 6β-hydroxylation of T and the 16α- and 7α-hydroxylation of DHEA.
“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
Prostate cells express CYP3A4 that can inactivate T by conversion to mainly 6βOH-T.
“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

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Steroid hydroxylation by human fetal CYP3A7 and human NADPH-cytochrome P450 reductase coexpressed in insect cells using baculovirus.
Ohmori, S., Fujiki, N., Nakasa, H., Nakamura, H., Ishii, I., Itahashi, K., & Kitada, M. (1998) · PubMed · Cited by 27 · see citing works
Interaction of CYP11B1 (cytochrome P‐45011β) with CYP11A1 (cytochrome P‐450scc) in COS‐1 cells
Cao, P., & Bernhardt, R. (1999) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.1999.00414.x · Cited by 26 · see citing works
A common CYP1B1 polymorphism is associated with 2-OHE1/16-OHE1 urinary estrone ratio
Paracchini, V., Pedotti, P., Raimondi, S., GARTE, S. J., Bradlow, H. L., Sepkovic, D. W., & Taioli, E. (2005) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm.2005.119 · Cited by 25 · see citing works
Comparison of Cytochrome P450 2C Subfamily Members in Terms of Drug Oxidation Rates and Substrate Inhibition
Niwa, T., & Yamazaki, H. (2012) · Current Drug Metabolism · doi:10.2174/138920012802850092 · Cited by 24 · see citing works
Comparison of the 17α-Hydroxylase/C17,20-Lyase Activities of Porcine, Guinea Pig and Bovine P450c17 Using Purified Recombinant Fusion Proteins Containing P450c17 Linked to NADPH-P450 Reductase
Shet, M. S., Fisher, C., Tremblay, Y., Bélanger, A., Conley, A. J., Mason, J. I., & Estabrook, R. W. (2007) · Drug Metabolism Reviews · doi:10.1080/03602530701468391 · Cited by 21 · see citing works
Comparison of CYP3A4 and CYP3A5: The Effects of Cytochrome b5 and NADPH-cytochrome P450 Reductase on Testosterone Hydroxylation Activities
Lee, S., & Goldstein, J. A. (2012) · Drug Metabolism and Pharmacokinetics · doi:10.2133/dmpk.dmpk-12-sh-030 · Cited by 20 · see citing works
Still another activity by the highly promiscuous enzyme CYP3A4: 25-hydroxylation of cholesterol
Diczfalusy, U., & Ingemar Björkhem, E. B. (2011) · Journal of Lipid Research · doi:10.1194/jlr.e017806 · Cited by 20 · see citing works
Comparison of Catalytic Properties of Cytochromes P450 3A4 and 3A5 by Molecular Docking Simulation
Niwa, T., Yasumura, M., Murayama, N., & Yamazaki, H. (2013) · Drug Metabolism Letters · doi:10.2174/1872312807666131229121228 · Cited by 18 · see citing works
Amino Acid Residues Affecting the Activities of Human Cytochrome P450 2C9 and 2C19
Niwa, T., Kageyama, A., Kishimoto, K., Yabusaki, Y., Ishibashi, F., & Katagiri, M. (2002) · Drug Metabolism and Disposition · doi:10.1124/dmd.30.8.931 · Cited by 16 · see citing works
New Aspects on Primary Aldosteronism
Enberg, U., Volpe, C., & Hamberger, B. (2003) · Neurochemical Research · doi:10.1023/a:1022341619943 · Cited by 15 · see citing works
Comparison of the Contributions of Cytochromes P450 3A4 and 3A5 in Drug Oxidation Rates and Substrate Inhibition
Niwa, T., Murayama, N., & Yamazaki, H. (2010) · Eisei kagaku · doi:10.1248/jhs.56.239 · Cited by 12 · see citing works
Association between urinary 6β-hydroxycortisol/cortisol ratio and CYP3A5 genotypes in a normotensive population
Rais, N., Hussain, A., Chawla, Y. K., & Kohli, K. K. (2012) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2012.842 · Cited by 10 · see citing works
Inhibition of Human Steroidogenic Cytochrome P450 c17 by 21-Hydroxypregnenolone and Related Steroid Hormones
Niwa, T., Imamura, H., & Katagiri, M. (2012) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b12-00080 · Cited by 2 · see citing works

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Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review
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 · see citing works
“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 · see citing works
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 · see citing works
“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.”
Proposed Key Characteristics of Male Reproductive Toxicants as an Approach for Organizing and Evaluating Mechanistic Evidence in Human Health Hazard Assessments
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 88 · see citing works
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 88 · see citing works
Human Family 1–4 cytochrome P450 enzymes involved in the metabolic activation of xenobiotic and physiological chemicals: an update
Rendić, S., & Guengerich, F. P. (2021) · Archives of Toxicology · doi:10.1007/s00204-020-02971-4 · Cited by 85 · see citing works
One Pot Use of Combilipases for Full Modification of Oils and Fats: Multifunctional and Heterogeneous Substrates
Arana‐Peña, S., Carballares, D., Berenguer‐Murcia, Á., Alcántara, A. R., Rodrigues, R. C., & Fernández‐Lafuente, R. (2020) · Catalysts · doi:10.3390/catal10060605 · Cited by 80 · see citing works
Oxidative Diversification of Steroids by Nature-Inspired Scanning Glycine Mutagenesis of P450BM3 (CYP102A1)
Chen, W.-Y., Fisher, M. J., Leung, A., Cao, Y., & Wong, L. (2020) · ACS Catalysis · doi:10.1021/acscatal.0c02077 · Cited by 69 · see citing works
Structural basis of steroid binding and oxidation by the cytochrome P450 CYP 109E1 from Bacillus megaterium
Jozwik, I. K., Kiss, F. M., Gricman, Ł., Abdulmughni, A., Brill, E., Zapp, J., Pleiss, J., Bernhardt, R., & Thunnissen, A. M. W. H. (2016) · FEBS Journal · doi:10.1111/febs.13911 · Cited by 60 · see citing works
Natural Products That Target Cancer Stem Cells.
Moselhy, J., Srinivasan, S., Ankem, M. K., & Damodaran, C. (2015) · PubMed · Cited by 57 · see citing works
Site-Selective and Product Chemoselective Aliphatic C–H Bond Hydroxylation of Polyhydroxylated Substrates
Borrell, M., Gil‐Caballero, S., Bietti, M., & Costas, M. (2020) · ACS Catalysis · doi:10.1021/acscatal.9b05423 · Cited by 57 · see citing works
CYP1B1 as a therapeutic target in cardio-oncology
Carrera, A. N., Grant, M. K. O., & Zordoky, B. N. M. (2020) · Clinical Science · doi:10.1042/cs20200310 · Cited by 44 · see citing works
Assembly and Evolution of Artificial Metalloenzymes within E. coli Nissle 1917 for Enantioselective and Site-Selective Functionalization of C─H and C═C Bonds
Liu, Z., Huang, J., Gu, Y., Clark, D. S., Mukhopadhyay, A., Keasling, J. D., & Hartwig, J. F. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.1c10975 · Cited by 44 · see citing works
Emerging roles for brain drug-metabolizing cytochrome P450 enzymes in neuropsychiatric conditions and responses to drugs
Toselli, F., Dodd, P. R., & Gillam, E. M. J. (2016) · Drug Metabolism Reviews · doi:10.1080/03602532.2016.1221960 · Cited by 36 · see citing works
A High‐Throughput Mass Spectrometric Enzyme Activity Assay Enabling the Discovery of Cytochrome P450 Biocatalysts
de Rond, T., Gao, J., Zargar, A., de Raad, M., Cunha, J., Northen, T. R., & Keasling, J. D. (2019) · Angewandte Chemie International Edition · doi:10.1002/anie.201901782 · Cited by 36 · see citing works
Qi Gong Wan ameliorates adipocyte hypertrophy and inflammation in adipose tissue in a PCOS mouse model through the Nrf2/HO-1/Cyp1b1 pathway: Integrating network pharmacology and experimental validation in vivo
Zheng, R., Shen, H., Li, J., Zhao, J., Lu, L., Hu, M., Lin, Z., Ma, H., Tan, H., Hu, M., et al. (2022) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2022.115824 · Cited by 35 · see citing works
Effects of frequently applied carbon monoxide releasing molecules (CORMs) in typical CO-sensitive model systems – A comparative in vitro study
Stucki, D., Krahl, H., Walter, M., Steinhausen, J., Hommel, K., Brenneisen, P., & Stahl, W. (2020) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2020.108383 · Cited by 35 · see citing works
Dehydroepiandrosterone and age-related musculoskeletal diseases: Connections and therapeutic implications
Huang, K., Cai, H., Bao, J., & Wu, L. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101132 · Cited by 36 · see citing works
Gut Microbiome Alters the Activity of Liver Cytochromes P450 in Mice With Sex-Dependent Differences
Jourová, L., Vavrečková, M., Zemanová, N., Anzenbacher, P., Langová, K., Hermanová, P. P., Hudcovic, T., & Anzenbacherová, E. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.01303 · Cited by 33 · see citing works
The consequence and mechanism of dietary flavonoids on androgen profiles and disorders amelioration
Hu, X., Li, X., Deng, P., Zhang, Y., Liu, R., Cai, D., Xu, Q., Jiang, X., Sun, J., & Bai, W. (2022) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2022.2090893 · Cited by 32 · see citing works
Selective Hydroxylation of C(sp3)−H Bonds in Steroids
Abas, H., Blencowe, P., Brookfield, J. L., & Harwood, L. A. (2023) · Chemistry - A European Journal · doi:10.1002/chem.202301066 · Cited by 31 · see citing works
Substrate Hunting for the Myxobacterial CYP260A1 Revealed New 1α‐Hydroxylated Products from C‐19 Steroids
Khatri, Y., Ringle, M., Lisurek, M., von Kries, J. P., Zapp, J., & Bernhardt, R. (2015) · ChemBioChem · doi:10.1002/cbic.201500420 · Cited by 31 · see citing works
Genotoxicity of ortho-quinones: reactive oxygen species versus covalent modification
Penning, T. M. (2017) · Toxicology Research · doi:10.1039/c7tx00223h · Cited by 29 · see citing works
Comparison of steroid hormone hydroxylation mediated by cytochrome P450 3A subfamilies
Niwa, T., Okamoto, A., Narita, K., Toyota, M., Kato, K., Kobayashi, K., & Sasaki, S. (2020) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2020.108283 · Cited by 28 · see citing works
Effect of penicillin-based antibiotics, amoxicillin, ampicillin, and piperacillin, on drug-metabolizing activities of human hepatic cytochromes P450
Niwa, T., Morimoto, M., Hirai, T., Hata, T., Hayashi, M., & Imagawa, Y. (2016) · The Journal of Toxicological Sciences · doi:10.2131/jts.41.143 · Cited by 28 · see citing works
A Naturally Occurring Isoform-Specific Probe for Highly Selective and Sensitive Detection of Human Cytochrome P450 3A5
Wu, J.-J., Cao, Y., Feng, L., He, Y., Hong, J. Y., Dou, T., Wang, P., Hao, D., Ge, G., & Yang, L. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00001 · Cited by 28 · see citing works
Continuum of Host-Gut Microbial Co-metabolism: Host CYP3A4/3A7 are Responsible for Tertiary Oxidations of Deoxycholate Species
Zhang, J., Gao, L.-Z., Chen, Y.-J., Zhu, P.-P., Yin, S.-S., Su, M., Ni, Y., Miao, J., Wu, W.-L., Chen, H., et al. (2019) · Drug Metabolism and Disposition · doi:10.1124/dmd.118.085670 · Cited by 28 · see citing works
Marmoset Cytochrome P450 3A4 Ortholog Expressed in Liver and Small-Intestine Tissues Efficiently Metabolizes Midazolam, Alprazolam, Nifedipine, and Testosterone
Uehara, S., Uno, Y., Nakanishi, K., Ishii, S., Inoue, T., Sasaki, E., & Yamazaki, H. (2017) · Drug Metabolism and Disposition · doi:10.1124/dmd.116.074898 · Cited by 26 · see citing works
Light-driven hydroxylation of testosterone by Synechocystis sp. PCC 6803 expressing the heterologous CYP450 monooxygenase CYP110D1
Mascia, F., Pereira, S. B., Pacheco, C. C., Oliveira, P., Solarczek, J., Schallmey, A., Kourist, R., Alphand, V., & Tamagnini, P. (2022) · Green Chemistry · doi:10.1039/d1gc04714k · Cited by 24 · see citing works
Fast steroid hormone metabolism assays with electrochemical liver microsomal bioreactor based on polydopamine encapsulated gold-graphene nanocomposite
Xu, X., Bai, G., Song, L., Zheng, Q., Yao, Y., Liu, S., & Yao, C. (2017) · Electrochimica Acta · doi:10.1016/j.electacta.2017.11.195 · Cited by 24 · see citing works
Polydopamine functionalized nanoporous graphene foam as nanoreactor for efficient electrode-driven metabolism of steroid hormones
Xu, X., Zheng, Q., Bai, G., Dai, Q., Cao, X., Yao, Y., Liu, S., & Yao, C. (2018) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2018.08.009 · Cited by 24 · see citing works
The regulation of liver cytochrome P450 expression and activity by the brain serotonergic system in different experimental models
Bromek, E., & Daniel, W. A. (2021) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2021.1872543 · Cited by 24 · see citing works
Cytochrome P450 Monooxygenases Catalyse Steroid Nucleus Hydroxylation with Regio‐ and Stereo‐Selectivity
Zhu, R., Liu, Y., Yang, Y., Min, Q., Li, H., & Chen, L. (2022) · Advanced Synthesis & Catalysis · doi:10.1002/adsc.202200210 · Cited by 23 · see citing works
CYP27A1 inhibits proliferation and migration of clear cell renal cell carcinoma via activation of LXRs/ABCA1
Liang, Z., Jiao, W., Wang, L., Chen, Y., Li, D., Zhang, Z., Zhang, Z., Liang, Y., & Niu, H. (2022) · Experimental Cell Research · doi:10.1016/j.yexcr.2022.113279 · Cited by 22 · see citing works
Stereoselective Oxidation Kinetics of Deoxycholate in Recombinant and Microsomal CYP3A Enzymes: Deoxycholate 19-Hydroxylation Is an In Vitro Marker of CYP3A7 Activity
Chen, Y., Zhang, J., Zhu, P.-P., Xian-wen, T., Lin, Q.-H., Wang, W., Yin, S.-S., Gao, L.-Z., Su, M., Liu, C., et al. (2019) · Drug Metabolism and Disposition · doi:10.1124/dmd.119.086637 · Cited by 21 · see citing works
A CYPome-wide study reveals new potential players in the pathogenesis of Parkinson’s disease
Hartz, P., Fehlmann, T., Wagenpfeil, G., Unger, M. M., & Bernhardt, R. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1094265 · Cited by 21 · see citing works
Comparison of Steroid Hormone Hydroxylations by and Docking to Human Cytochromes P450 3A4 and 3A5
Niwa, T., Narita, K., Okamoto, A., Murayama, N., & Yamazaki, H. (2019) · Journal of Pharmacy & Pharmaceutical Sciences · doi:10.18433/jpps30558 · Cited by 21 · see citing works
Steroids hydroxylation catalyzed by the monooxygenase mutant 139-3 from Bacillus megaterium BM3
Liu, X., & Kong, J. (2017) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2017.04.006 · Cited by 20 · see citing works
Effects of xenobiotics on CYP1 enzyme-mediated biotransformation and bioactivation of estradiol
Mao, X., Li, H., & Zheng, J. (2023) · Drug Metabolism Reviews · doi:10.1080/03602532.2023.2177671 · Cited by 20 · see citing works
Case Study in 21st Century Ecotoxicology: Using In Vitro Aromatase Inhibition Data to Predict Short-Term In Vivo Responses in Adult Female Fish
Villeneuve, D. L., Blackwell, B. R., Cavallin, J. E., Cheng, W., Feifarek, D. J., Jensen, K. M., Kahl, M. W., Milsk, R. Y., Poole, S. T., Randolph, E. C., et al. (2020) · Environmental Toxicology and Chemistry · doi:10.1002/etc.4968 · Cited by 20 · see citing works
AhR governs lipid metabolism: the role of gut microbiota
Zheng, W., Liu, M., Lv, X., He, C., Yin, J., & Ma, J. (2025) · Frontiers in Microbiology · doi:10.3389/fmicb.2025.1442282 · Cited by 21 · see citing works
Surface charge-controlled electron transfer and catalytic behavior of immobilized cytochrome P450 BM3 inside dendritic mesoporous silica nanoparticles
Dai, Q., Yang, L., Wang, Y., Cao, X., Yao, C., & Xu, X. (2020) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-020-02727-0 · Cited by 19 · see citing works
Regio- and stereoselective hydroxylation of testosterone by a novel cytochrome P450 154C2 from Streptomyces avermitilis
Wang, Q., Ma, B., Fushinobu, S., Zhang, C., & Xu, L. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.11.091 · Cited by 18 · see citing works
Characterization of a Novel CYP1A2 Knockout Rat Model Constructed by CRISPR/Cas9
Sun, D., Lu, J., Zhang, Y., Liu, J., Liu, Z., Yao, B., Guo, Y., & Wang, X. (2021) · Drug Metabolism and Disposition · doi:10.1124/dmd.121.000403 · Cited by 18 · see citing works
Predicting disruptions to drug pharmacokinetics and the risk of adverse drug reactions in non-alcoholic steatohepatitis patients
Marie, S., Frost, K. L., Hau, R. K., Martinez-Guerrero, L., Izu, J. M., Myers, C. M., Wright, S. H., & Cherrington, N. J. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.08.018 · Cited by 18 · see citing works
Structure–function analysis for the hydroxylation of Δ4 C21‐steroids by the myxobacterial CYP260B1
Salamanca-Pinzon, S. G., Khatri, Y., Carius, Y., Keller, L., Müller, R., Lancaster, C. R. D., & Bernhardt, R. (2016) · FEBS Letters · doi:10.1002/1873-3468.12217 · Cited by 18 · see citing works
High hepatic and plasma exposures of atorvastatin in subjects harboring impaired cytochrome P450 3A4∗16 modeled after virtual administrations and possibly associated with statin intolerance found in the Japanese adverse drug event report database
Adachi, K., Ohyama, K., Tanaka, Y., Sato, T., Murayama, N., Shimizu, M., Saito, Y., & Yamazaki, H. (2022) · Drug Metabolism and Pharmacokinetics · doi:10.1016/j.dmpk.2022.100486 · Cited by 17 · see citing works
Characterization of Maternal and Fetal CYP3A-Mediated Progesterone Metabolism
Quinney, S. K., Benjamin, T. D., Zheng, X., & Patil, A. S. (2017) · Fetal and Pediatric Pathology · doi:10.1080/15513815.2017.1354411 · Cited by 16 · see citing works
The Effect of Genetic Polymorphism on the Inhibition of Azole Antifungal Agents Against CYP2C9-Mediated Metabolism
Niwa, T., & Hata, T. (2016) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2016.01.007 · Cited by 15 · see citing works
Effect of genetic polymorphism on the inhibition of dopamine formation from p -tyramine catalyzed by brain cytochrome P450 2D6
Niwa, T., Shizuku, M., & Yamano, K. (2017) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2017.03.009 · Cited by 15 · see citing works
Anti-androgenic effect of 6-formylindolo[3,2-b]carbazole (FICZ) in LNCaP cells is mediated by the aryl hydrocarbon-androgen receptors cross-talk
Arabnezhad, M., Montazeri‐Najafabady, N., Chatrabnous, N., Ghaffarian‐Bahraman, A., & Mohammadi‐Bardbori, A. (2019) · Steroids · doi:10.1016/j.steroids.2019.108508 · Cited by 15 · see citing works
Explorative study on the anticancer activity, selectivity and metabolic stability of related analogs of aminosteroid RM-133
Perreault, M., Maltais, R., Dutour, R., & Poirier, D. (2016) · Steroids · doi:10.1016/j.steroids.2016.08.015 · Cited by 15 · see citing works
Novel regulation of the transcription factor ZHX2 by N-terminal methylation
Conner, M. M., Parker, H. V., Falcone, D. R., Chung, G., & Tooley, C. E. S. (2022) · Transcription · doi:10.1080/21541264.2022.2079184 · Cited by 14 · see citing works
Structure-based virtual screening of CYP1A1 inhibitors: towards rapid tier-one assessment of potential developmental toxicants
Goh, J. J. N., Behn, J., Chong, C., Zhong, G., Maurer‐Stroh, S., Fan, H., & Loo, L. (2021) · Archives of Toxicology · doi:10.1007/s00204-021-03111-2 · Cited by 13 · see citing works
Novel Cytochrome P450 2C94 Functionally Metabolizes Diclofenac and Omeprazole in Dogs
Uno, Y., Morikuni, S., Shiraishi, M., Asano, A., Murayama, N., & Yamazaki, H. (2023) · Drug Metabolism and Disposition · doi:10.1124/dmd.122.001236 · Cited by 13 · see citing works
Comparative transcriptome analysis between rhesus macaques (Macaca mulatta) and crab-eating macaques (M. fascicularis)
Mao, Y., 中国科学院神经科学研究所神经科学国家重点实验室, 脑., Li, Y., Yang, Z., Xu, N., Zhang, S., Wang, X., Yang, X., Sun, Q., Mao, Y., et al. (2023) · 动物学研究 · doi:10.24272/j.issn.2095-8137.2023.322 · Cited by 12 · see citing works
Identification of an important function of CYP123: Role in the monooxygenase activity in a novel estradiol degradation pathway in bacteria
Ye, X., Peng, T., Li, Y., Huang, T., Wang, H., & Hu, Z. (2021) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2021.106025 · Cited by 13 · see citing works
Invited review: Cytochrome P450 enzyme involvement in health and inflammatory-based diseases of dairy cattle
Kuhn, M. J., Mavangira, V., & Sordillo, L. M. (2020) · Journal of Dairy Science · doi:10.3168/jds.2020-18997 · Cited by 14 · see citing works
Identification of a less toxic vinca alkaloid derivative for use as a chemotherapeutic agent, based on in silico structural insights and metabolic interactions with CYP3A4 and CYP3A5
Saba, N., & Seal, A. (2018) · Journal of Molecular Modeling · doi:10.1007/s00894-018-3611-1 · Cited by 11 · see citing works
Effects of dietary supplementation of N‐carbamylglutamate on the haematology parameters, secondary sexual characteristics and testicular gene expression in roosters
Ma, W., Dang, D. X., Zhang, J., Wang, C., & Li, D. (2022) · Journal of Animal Physiology and Animal Nutrition · doi:10.1111/jpn.13714 · Cited by 11 · see citing works
CYP2S1 and CYP2W1 expression is associated with patient survival in breast cancer
Aiyappa‐Maudsley, R., Storr, S. J., Rakha, E. A., Green, A. R., Ellis, I. O., & Martin, S. G. (2022) · The Journal of Pathology Clinical Research · doi:10.1002/cjp2.291 · Cited by 11 · see citing works
Effects of Shengmai San on key enzymes involved in hepatic and intestinal drug metabolism in rats
Chiang, T.-Y., Wang, H.-J., Wang, Y.-C., Tan, E. C., Lee, I., Yun, C., & Ueng, Y. (2021) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2021.113914 · Cited by 11 · see citing works
Mechanistic Insights into the Regio‐ and Stereoselectivities of Testosterone and Dihydrotestosterone Hydroxylation Catalyzed by CYP3A4 and CYP19A1
Li, J., Tang, Y., Li, W., & Tu, Y. (2020) · Chemistry - A European Journal · doi:10.1002/chem.201905272 · Cited by 11 · see citing works
H 2 O 2 -Driven Hydroxylation of Steroids Catalyzed by Cytochrome P450 CYP105D18: Exploration of the Substrate Access Channel
Pardhe, B. D., Kwon, K. P., Park, J. K., Lee, J. H., & Oh, T. (2022) · Applied and Environmental Microbiology · doi:10.1128/aem.01585-22 · Cited by 11 · see citing works
A patent review of CYP3A4 inhibitors (2018 – present)
Tu, D., Hu, X., Lei, J.-X., Liu, S., Xiao, Z.-P., Yang, L., & Ge, G. (2025) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2025.2470294 · Cited by 10 · see citing works
From fallopian tube epithelium to high-grade serous ovarian cancer: A single-cell resolution review of sex steroid hormone signaling
Gjorgoska, M., & Rižner, T. L. (2024) · Progress in Lipid Research · doi:10.1016/j.plipres.2024.101302 · Cited by 9 · see citing works
Substrate Specificity of Human Cytochrome P450 (CYP) 2C Subfamily and Effect of Azole Antifungal Agents on CYP2C8
Niwa, T., & Imagawa, Y. (2016) · Journal of Pharmacy & Pharmaceutical Sciences · doi:10.18433/j31s53 · Cited by 9 · see citing works
The correlation between the expression of genes involved in drug metabolism and the blood level of tacrolimus in liver transplant receipts
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Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones
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Authors: Niwa, T., Murayama, N., Imagawa, Y., & Yamazaki, H.
Affiliations: Shujitsu University (JP)
Showa Pharmaceutical University (JP)
Corresponding author: Yamazaki, Hiroshi
ORCID: Niwa, Toshiro
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
DOI: 10.3109/03602532.2015.1011658
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
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › 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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Regioselective hydroxylation of steroid hormones by human cytochromes P450

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