Role of P450 enzymes of the Cyp2abfgs gene subfamilies in tobacco smoke-induced lung tumorigenesis in mice

Abstract Many chemical carcinogens in tobacco smoke require bioactivation by cytochrome P450 enzymes. While the roles of P450 enzymes in carcinogenesis have been demonstrated in vivo using several individual carcinogens at relatively high doses, no data has been reported on their contributions to carcinogenesis induced by tobacco smoke, a complex mixture of 4000 compounds. The present study aims to address this important knowledge gap, using mice deficient in the expression of enzymes of the Cyp2abfgs gene subfamilies, which are known to bioactivate multiple chemical carcinogens in tobacco smoke. Male and female wild-type (WT) and Cyp2abfgs-null mice on the A/J genetic background were exposed to environmental tobacco smoke (ETS), a mixture of mainstream and sidestream smoke, for 6 hours/day, 5 days/week, for 5 months, at a target dose of 0 or 120 mg/m3 suspended total particulate matter. All mice were returned to filtered air (FA) for 4 months after cessation of ETS exposure. At approximately 11 months of age, mice were euthanized, and lungs were collected for tumor enumeration. ETS exposure increased tumor multiplicity (number of tumors per lung) in WT mice by 2.5-fold (p0.0001), but only by 1.7-fold in Cyp2abfgs-null mice (p0.001), compared to FA-exposed mice (n=∼180 per group, male and female). Multiplicity of ETS-induced tumors was significantly reduced (by 50%; p0.01) in Cyp2abfgs-null relative to WT mice. These results demonstrate for the first time, in vivo, that bioactivation of ETS constituents by P450 enzymes, of the Cyp2abfgs gene subfamilies, play an important role in tobacco-smoke induced lung tumorigenesis in mice.