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 metabol ism of many drugs and in the activation of chemical carcinogens. The a ctivities of two cytochromes P450 (CYP2D6 and CYP2C19) are under indep endent monogenic control and exhibit marked genetic polymorphisms. Thr ee to eight per cent of white Caucasians are termed poor metabolisers (PMs) because of an inability to metabolize debrisoquine or mephenytoi n, 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 in vestigate the relationship between breast cancer and drug oxidation ph enotype and genotype. One hundred and five women with histologically p roven breast cancer and a control group of 223 women with benign breas t disease were recruited. Each subject was given 10 mg debrisoquine he misulphate and 100 mg mephenytoin p.o. and urine was collected for 8 h . A blood sample was taken for CYP2D6 genotyping. There was no signifi cant difference in the median debrisoquine/4-hydroxydebrisoquine ratio between the breast cancer patients (0.73) and the controls (0.59). Si milarly, the prevalence of the PM phenotype did not differ significant ly between the malignant (11%) and control (12%) groups. There was no significant difference in the frequency of the CYP2D6B mutant allele b etween 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 (0.2 7) groups (P = 0.048) but not between the median mephenytoin/4'-hydrox ymephenytoin ratios (malignant = 0.00243; benign = 0.00163). The distr ibutions of the log(10) mephenyloin/4'-hydroxymephenytoin ratios appea red bimodal unlike those of the S-/R-mephenytoin ratios. The prevalenc e of the PM phenotype for mephenytoin did not differ significantly bet ween 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.