METABOLIC POLYMORPHISM AFFECTING DNA-BINDING AND EXCRETION OF CARCINOGENS IN HUMANS

A case-control study on lung cancer patients demonstrated the pronounc ed effect of tobacco smoke on pulmonary carcinogen metabolism and sugg ested the existence of a metabolic phenotype at higher risk for tobacc o-associated lung cancer. Lung cancer patients who were recent smokers showed in their lungs (i) significantly induced CYP1A1-related enzyme activity vs smoking non-lung cancer patients; (ii) increased benzo(a) pyrene (BP) tetrol formation from BP 7,8-diol by lung microsomes; and (iii) high levels of cytochrome P4501a1 by immunohistochemical stainin g. Levels of bulky aromatic DNA adducts (by P-32-postlabelling) and of BP-diol-epoxide (BPDE) adducts (by HPCL/fluorometry) were quantified in lung parenchyma. Aryl hydrocarbon hydroxylase activity and the leve l of BPDE-DNA adducts (r = 0.91; p < 0.001) and to a lesser degree bul ky DNA adducts were correlated. Thus pulmonary CYP1A1 expression (indu cibility) controls in part polycyclic aromatic hydrocarbon-DNA adduct formation in tobacco smokers and, therefore, appears to be associated with lung cancer risk. High risk subjects for lung cancer among smoker s may be identifiable through genotyping for polymorphic drug metaboli zing enzymes in combination with molecular dosimetry of carcinogen-DNA adducts and mutation analysis in target (surrogate) cells. Such studi es in a Finnish cohort of lung cancer patients and controls are in pro gress. Interim results of the effect of metabolic polymorphism on the level of PAH-DNA adducts and on the excretion of mutagens in urine are summarized.