Role of Polymorphic Human Cytochrome P450 Enzymes in Estrone Oxidation
Open Access
- 1 March 2006
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Epidemiology, Biomarkers & Prevention
- Vol. 15 (3), 551-558
- https://doi.org/10.1158/1055-9965.epi-05-0801
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 16α-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 16α-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 16α-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. (Cancer Epidemiol Biomarkers Prev 2006;15(3):551–8)Keywords
This publication has 50 references indexed in Scilit:
- Association of CYP1A1 Polymorphisms with Differential Metabolic Activation of 17β-Estradiol and EstroneCancer Research, 2005
- A Unifying Mechanism in the Initiation of Cancer and Other Diseases by Catechol QuinonesAnnals of the New York Academy of Sciences, 2004
- Cytochrome P450 1B1 gene polymorphisms and postmenopausal breast cancer riskCarcinogenesis: Integrative Cancer Research, 2003
- Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised womenThe Lancet, 1998
- Functional role of estrogen metabolism in target cells: review and perspectivesCarcinogenesis: Integrative Cancer Research, 1998
- Dual role of oestrogens as hormones and pro-carcinogens: tumour initiation by metabolic activation of oestrogensEuropean Journal Of Cancer Prevention, 1997
- Expression of glutathione S-transferases and cytochrome P450 in normal and tumor breast tissueCarcinogenesis: Integrative Cancer Research, 1990
- Free radical generation by redox cycling of estrogensFree Radical Biology & Medicine, 1990
- Binding of 2-hydroxyestradiol and 4-hydroxyestradiol to estrogen receptors from human breast cancersJournal of Steroid Biochemistry, 1989
- Carcinogenicity of catechol estrogens in Syrian hamstersJournal of Steroid Biochemistry, 1986