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Summary The role of two common polymorphisms of enzymes involved in the metabolism of drugs and carcinogens was studied in relation to prostate cancer. The gene encoding one of these enzymes (NAT2) is located in an area where frequent allelic loss occurs in prostate cancer. Mutations at the genes CYP2D6 and NAT2 were analysed by allele-specific polymerase chain reaction and restriction mapping in DNA from 94 subjects with prostate cancer and 160 male healthy control subjects. Eleven prostate specimens were analysed for genotype and enzymatic activities NAT2, CYP2D6 and CYP3A by using the enzyme-specific substrates sulphamethazine and dextromethorphan. Enzyme activities with substrate specificities corresponding to NAT2, CYP2D6 and CYP3A are present in human prostate tissue, with mean ± s.d. activities of 4.8 ± 4.4 pmol min-' mg-' protein, 156 ± 91 and 112 ± 72 nmol min-' mg-' protein respectively. The Km, values for the prostate CYP2D6 and CYP3A enzyme activities corresponded to that of liver CYP2D6 and CYP3A activities, and the CYP2D6 enzyme activity is related to the CYP2D6 genotype. The N-acetyftransferase, in contrast, had a higher Km than NAT2 and was independent of the NAT2 genotype. The CYP2D6 and CYP3A enzymes, and an N-acetyttransferase activity that is independent of the regulation of the NAT2 gene. are expressed in human prostate tissue. The presence of carcinogen-metabolizing enzymes in human prostate with a high interindividual variability may be involved in the regulation of local levels of carcinogens and mutagens and may underie interindividual differences in cancer susceptibility. 1362 JAG Agundez et al due to a strong local effect on the actixation or deactivation of carcinogens in situ. For instance. it has been shovA-n that N-acetvltransferase polx morphism play s a relevant role in the formation of 2-aminofluorene-DNA adducts in tumour target organs (Feng et al. 1996). In an attempt to elucidate the events that occur as previous steps to prostate carcinogenesis. x e hax e studied A hether the poix-morphic enzymes CYP2D6 and NAT2 are actix ely expressed in human prostate tissue. as well as the impact of such genetic polx morphisms in prostate cancer susceptibility. In order to ex aluate w-hether allelic loss of these genes occurs in adenomatous prostate tissue. the occurrence of allelic losses at the CYP2D and .VA72 gene loci in prostate tissues was also studied. If the CYP2D6 enzyrme is functionally expressed in prostate. allelic loss of CYP2D6 could cause changes in local enzyme activity. modifving the local metabolism of carcinooens and mutarens. To our know-ledge. no studies involving allelic loss of the polymorphic gene CYP2D6 haxe been performed. This is also the first study inxolxing allelic loss of the NVA72 gene in prostate. Indeed only one study involvin2 allelic loss of NAT2 has been published. and it was performed in colon cancer (Hubbard et al. 1997). Keywords METHODS Patients and controlsAll the subjects included in this studx were unrelated v hite Spanish men. samples from t...

The cytochrome P₄₅₀ CYP2D6 is a polymorphic drug-metabolizing enzyme that is involved in the metabolism of several drugs and xenobiotics. Several independent studies indicate that the CYP2D6 metabolic status is a secondary factor in the risk of developing lung cancer, with individuals with high activity being at increased risk. The occurrence of functionally active duplications of the CYP2D6 gene is a phenomenon that affects 3–8% of Caucasians and up to 30% in some ethnic groups. These duplications cause ultrarapid metabolism of CYP2D6 substrates. In order to establish whether the highest CYP2D6 enzyme activity is associated with an increased risk of cancer, we analyzed the frequency of CYP2D6 gene duplications and enzyme-inactivating mutations in 199 Caucasian patients with lung or larynx cancer and in 335 healthy controls. A significantly increased frequency of carriers of the CYP2D6 gene duplication were found among lung and larynx cancer patients (13%), as compared with healthy controls (6.9%; p < 0.02). The frequency of the mutated active CYP2D6*9 allele was increased in lung cancer patients (p < 0.01) but not in larynx cancer patients. Global findings indicate that over 20% patients with lung or larynx cancer show CYP2D6 genotypes leading to ultrarapid metabolism or to the expression of an enzyme with altered kinetics (p < 0.01 vs. healthy controls). This may influence the metabolism of CYP2D6 substrates, including antineoplastic drugs and opioid derivatives used for pain relief in cancer patients. These patients would require higher doses than those considered as standard. We conclude that dosages for CYP2D6 substrates should be adapted to lung and larynx cancer patients.

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