Role of polymorphic human cytochrome P450 enzymes in estrone oxidation.
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.
Cribb
Alastair E
AE
Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward Island, Canada C1A 4P3. acribb@upei.ca
Knight
M Joy
MJ
Dryer
Dagny
D
Guernsey
Judy
J
Hender
Kimberly
K
Tesch
Marvin
M
Saleh
Tarek M
TM
D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004970:Estrone / Q000378:metabolism*; D005260:Female; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010084:Oxidation-Reduction; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D004970:Estrone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2