Cytochrome P450 2C19 (
CYP2C19) plays an important role in the metabolism of
xenobiotics and drugs and contributes to the catabolism of endogenous substrates like
estradiol. Genetic variability impacts expression and activity of
CYP2C19 and therefore can influence catabolism of
estrogens. In the present study we analyzed the association of three polymorphisms of
CYP2C19 namely
CYP2C19*2 (
CYP2C19_681_G>A, rs4244285),
CYP2C19*3 (
CYP2C19_636_G>A, rs57081121) and
CYP2C19*17 (
CYP2C19_-806_C>T, rs12248560), with
breast cancer susceptibility. We genotyped 1,015
breast cancer cases and 1,021 age-matched, population-based controls of the German GENICA study by matrix assisted
laser desorption/ionization time-of-flight mass spectrometry. Risk estimates were calculated by logistic regression. All tests were two-sided. We observed a decreased
breast cancer risk for carriers of the
CYP2C19*17 allele (OR 0.77, 95% CI: 0.65-0.93; P = 0.005). In subgroup analysis we observed a significant decreased
breast cancer risk for women using
hormone therapy for ten years or longer who were carriers of the
CYP2C19*17 allele (OR 0.57, 95% CI: 0.39-0.83; P = 0.003). Since
CYP2C19*17 defines an ultra rapid metabolizer phenotype we suggest that an increased catabolism of
estrogens by
CYP2C19 may lead to decreased
estrogen levels and therefore reduces
breast cancer risk. This protective effect seems to be stronger in combination with long-term intake of supplemental
estrogens during
hormone therapy.