EFFECTS OF TOBACCO-SMOKE ON THE GENE-EXPRESSION OF THE CYP1A, CYP2B, CYP2E, AND CYP3A SUBFAMILIES IN MOUSE-LIVER AND LUNG - RELATION TO SINGLE-STRAND BREAKS OF DNA

Cigarette smoking is a worldwide health problem and is the greatest ri sk factor for lung cancer. By activating procarcinogens, hepatic and e xtrahepatic cytochromes P450 can participate in lung carcinogenesis. T obacco smoke contains numerous cytochrome P450 inducers, substrates, a nd inhibitors. In the present study we investigated, in male NMRI mice , the effects of cigarette smoke on hepatic and pulmonary cytochrome P 450 expression and their possible role in the induction of DNA lesions such as DNA single strand breaks (SSB). Hepatic and pulmonary mouse c ytochrome P450 isozymes involved in carcinogenesis (Cyp1a, 2b, 2e, 3a) were differently induced by cigarette smoke. Cyp2e1 mRNA was dramatic ally enhanced (12.7-fold increase) while Cyp2b10 mRNA remained unchang ed and Cyp1a1 was decreased or not detected. Cyp3a protein and mRNA we re not detected in lung, suggesting that this isozyme is not expressed in mouse pulmonary tissue. The SSB of DNA increased in lung and liver treated mice. In contrast no modification was observed in lymphocytes that barely expressed cytochromes P450. Cimetidine and propylene glyc ol reduced SSB of DNA induced by smoking in liver and lung cells. The inhibition (-70%) observed in lung following treatment by propylene gl ycol, a CYP2E1 inhibitor, suggested that this isozyme is at least in p art involved in pulmonary DNA damage induced by tobacco smoke. The hig h concentration of CYP2E1 function and regulation in mammals suggests that this protein could be involved in pulmonary carcinogenesis in hum an smokers. (C) 1988 Academic Press.