Lack of relationships between the debrisoquine (CYP2D6) and mephenytion (CYP2C19) oxidation polymorphisms and susceptibility to breast cancer

The cytochrome P450 superfamily of enzymes is important in the metabolism of many drugs and in the activation of chemical carcinogens. The activities of two cytochromes P450 (CYP2D6 and CYP2C19) are under independent monogenic control and exhibit marked genetic polymorphisms. Three to eight per cent of white Caucasians are termed poor metabolisers (PMs) because of an inability to metabolize debrisoquine or mephenytoin, the prototype substrates of CYP2D6 and CYP2C19, respectively. Some previous studies have suggested that PMs of debrisoquine are at lower risk of developing lung cancer. The aim of the present study was to investigate the relationship between breast cancer and drug oxidation phenotype and genotype. One hundred and five women with histologically proven breast cancer and a control group of 223 women with benign breast disease were recruited. Each subject was given 10 mg debrisoquine hemisulphate and 100 mg mephenytoin p.o. and urine was collected for 8 h. A blood sample was taken for CYP2D6 genotyping. There was no significant difference in the median debrisoquine/4-hydroxydebrisoquine ratio between the breast cancer patients (0.73) and the controls (0.59). Similarly, the prevalence of the PM phenotype did not differ significantly between the malignant (11%) and control (12%) groups. There was no significant difference in the frequency of the CYP2D6B mutant allele between the two groups (malignant = 0.22, n = 30; BENIGN = 0.18, n = 93). A marginally significant difference was observed between the median S-/R-mephenytoin ratios for the breast cancer (0.37) and control (0.27) groups (P = 0.048) but not between the median mephenytoin/4′-hydroxymephenytoin ratios (malignant = 0.00243; BENIGN = 0.00163). The distributions of the log10 mephenytoin/4′-hydroxymephenytoin ratios appeared bimodal unlike those of the S-/R-mephenytoin ratios. The prevalence of the PM phenotype for mephenytoin did not differ significantly between the patients with breast cancer (5%) and the control group (4%). In conclusion, neither the debrisoquine nor the mephenytoin oxidation polymorphism appears to be related to susceptibility to breast cancer.