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Role of polymorphic human cytochrome P450 enzymes in estrone oxidation.
Cancer Epidemiol Biomarkers Prev. 2006 Mar; 15(3):551-8.CE

Abstract

Estrogen and its metabolites are believed to play important roles in breast cancer. The influence of genetic polymorphisms in the enzymes responsible for formation and disposition of estrogen on breast cancer risk may shed light on the importance of estrogen metabolites in this disease. However, for such studies to be valid, it is important to correctly identify the enzymes involved in estrogen bioactivation. Therefore, we assessed the human cytochrome P450-dependent oxidation of estrone using substrate concentrations that more closely approximate the maximum expected concentrations in breast tissue. The in vitro metabolism of estrone by recombinant human cytochrome P450 enzymes and human liver microsomes was studied. The formation of estrone metabolites (2-hydroxyestrone, 4-hydroxyestrone, and 16alpha-hydroxyestrone) was monitored by high-performance liquid chromatography. 2-Hydroxyestrone formation was catalyzed predominantly by CYP1A2, CYP1A1, and CYP1B1 enzymes; 4-hydroxyestrone formation was catalyzed predominantly by CYP1B1, CYP1A2, and CYP1A1 enzymes; and 16alpha-hydroxyestrone formation was catalyzed predominantly by CYP2C19, CYP1A1, and CYP3A5. This study confirms the important role of members of the CYP1 family in the 2-hydroxylation and 4-hydroxylation of estrone, but the enzymes identified as responsible for the 16alpha-hydroxylation of estrone are different from those previously identified. The relative importance of these enzymes in vivo would depend on the specific tissue expression of the enzymes. These enzymes are all known to be genetically variant in the human population, and additional studies to assess the role CYP1A2, CYP2C19, and CYP3A5 in breast cancer risk are indicated.

Authors+Show Affiliations

Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward Island, Canada C1A 4P3. acribb@upei.caNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16537715

Citation

Cribb, Alastair E., et al. "Role of Polymorphic Human Cytochrome P450 Enzymes in Estrone Oxidation." Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored By the American Society of Preventive Oncology, vol. 15, no. 3, 2006, pp. 551-8.
Cribb AE, Knight MJ, Dryer D, et al. Role of polymorphic human cytochrome P450 enzymes in estrone oxidation. Cancer Epidemiol Biomarkers Prev. 2006;15(3):551-8.
Cribb, A. E., Knight, M. J., Dryer, D., Guernsey, J., Hender, K., Tesch, M., & Saleh, T. M. (2006). Role of polymorphic human cytochrome P450 enzymes in estrone oxidation. Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored By the American Society of Preventive Oncology, 15(3), 551-8.
Cribb AE, et al. Role of Polymorphic Human Cytochrome P450 Enzymes in Estrone Oxidation. Cancer Epidemiol Biomarkers Prev. 2006;15(3):551-8. PubMed PMID: 16537715.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of polymorphic human cytochrome P450 enzymes in estrone oxidation. AU - Cribb,Alastair E, AU - Knight,M Joy, AU - Dryer,Dagny, AU - Guernsey,Judy, AU - Hender,Kimberly, AU - Tesch,Marvin, AU - Saleh,Tarek M, PY - 2006/3/16/pubmed PY - 2006/7/20/medline PY - 2006/3/16/entrez SP - 551 EP - 8 JF - Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology JO - Cancer Epidemiol Biomarkers Prev VL - 15 IS - 3 N2 - Estrogen and its metabolites are believed to play important roles in breast cancer. The influence of genetic polymorphisms in the enzymes responsible for formation and disposition of estrogen on breast cancer risk may shed light on the importance of estrogen metabolites in this disease. However, for such studies to be valid, it is important to correctly identify the enzymes involved in estrogen bioactivation. Therefore, we assessed the human cytochrome P450-dependent oxidation of estrone using substrate concentrations that more closely approximate the maximum expected concentrations in breast tissue. The in vitro metabolism of estrone by recombinant human cytochrome P450 enzymes and human liver microsomes was studied. The formation of estrone metabolites (2-hydroxyestrone, 4-hydroxyestrone, and 16alpha-hydroxyestrone) was monitored by high-performance liquid chromatography. 2-Hydroxyestrone formation was catalyzed predominantly by CYP1A2, CYP1A1, and CYP1B1 enzymes; 4-hydroxyestrone formation was catalyzed predominantly by CYP1B1, CYP1A2, and CYP1A1 enzymes; and 16alpha-hydroxyestrone formation was catalyzed predominantly by CYP2C19, CYP1A1, and CYP3A5. This study confirms the important role of members of the CYP1 family in the 2-hydroxylation and 4-hydroxylation of estrone, but the enzymes identified as responsible for the 16alpha-hydroxylation of estrone are different from those previously identified. The relative importance of these enzymes in vivo would depend on the specific tissue expression of the enzymes. These enzymes are all known to be genetically variant in the human population, and additional studies to assess the role CYP1A2, CYP2C19, and CYP3A5 in breast cancer risk are indicated. SN - 1055-9965 UR - https://www.unboundmedicine.com/medline/citation/16537715/Role_of_polymorphic_human_cytochrome_P450_enzymes_in_estrone_oxidation_ L2 - http://cebp.aacrjournals.org/cgi/pmidlookup?view=long&pmid=16537715 DB - PRIME DP - Unbound Medicine ER -