Role of CYP2A5 in the bioactivation of the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in mice.

ABSTRACT: The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent lung carcinogen. Previously, we have demonstrated that NNK-induced lung tumorigenesis in mice depends on target-tissue bioactivation by pulmonary cytochrome P450 (P450) enzymes. The present study was designed to test the hypothesis that mouse CYP2A5 plays an essential role in NNK bioactivation in mouse lung. The role of CYP2A5 in NNK bioactivation was studied both in vitro and in vivo, by comparing the kinetic parameters of microsomal NNK metabolism and tissue levels of O(6)-methylguanine (O(6)-mG) (the DNA adduct highly correlated with lung tumorigenesis) between wild-type (WT) and Cyp2a5-null mice. In both liver and lung microsomes, the loss of CYP2A5 resulted in significant increases in the

SUBMITTER: Zhou X 

PROVIDER: S-EPMC3310698 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature