Biotransformation of estradiol by explant culture of human mammary tissue.
In vivo experiments on strains of mice that differ in the risk of developing mammary cancer have demonstrated a correlation between the extent of 16 alpha-hydroxylation of estradiol and incidence of mammary cancer. The ability of human mammary terminal duct lobular unit (TDLU), the site of neoplastic transformation, to metabolize estradiol or to accumulate estradiol metabolites has not been unequivocally established. Using a newly developed human mammary TDLU explant culture system and a radiometric assay for estradiol metabolism, we compared the site-specific metabolism of estradiol by the 17-oxidation, 2-hydroxylation, and 16 alpha-hydroxylation pathways in noninvolved human mammary tissue. The relative extent of estradiol 16 alpha-hydroxylation was found to be increased in TDLU from patients in the luteal phase of the menstrual cycle in relation to either those from patients in the follicular phase or from postmenopausal subjects. This study demonstrates that TDLU can metabolize estradiol extrahepatically and that 16 alpha-hydroxylation in the target tissue is dependent on the phase of the menstrual cycle. Furthermore, the specific, risk-related increase in 16 alpha-hydroxylation suggests that intrinsic metabolic ability of the target tissue leading to the formation of 16 alpha-hydroxyestrone from estradiol may be a determinant in, or a marker for, the relative risk of developing mammary cancer.
Telang
N T
NT
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York New York 10021.
Axelrod
D M
DM
Wong
G Y
GY
Bradlow
H L
HL
Osborne
M P
MP
D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation / Q000502:physiology; D001940:Breast / Q000378:metabolism*; D001943:Breast Neoplasms / Q000209:etiology / Q000378:metabolism*; D002470:Cell Survival; D046508:Culture Techniques; D019363:Cytochrome P-450 CYP1A1; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D006801:Humans; D008597:Menstrual Cycle / Q000378:metabolism; D010084:Oxidation-Reduction; D012307:Risk Factors; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000378:metabolism
D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D019363:Cytochrome P-450 CYP1A1; D065727:Cytochrome P-450 CYP2C8; D039181:Steroid 16-alpha-Hydroxylase; C020120:estrogen 2-hydroxylase