Hepatic CYPs involved in both the detoxification and metabolic activation of many carcinogens.In order to reveal the role of hepatic cytochrome P450 in hepatic versus extra-hepatic metabolism of carcinogens, we generated a new hepatic P450 reductase null (HRN) gpt delta transgenic mouse model in which cytochrome P450 oxidoreductase, the unique electron donor to CYPs, is deleted specifically in hepatocytes.This deletion results in the loss of essentially all hepatic CYPs functions of gpt delta transgenic mouse.In the present study, we used two well-studied carcinogens, benzo[a]pyrene (BaP) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to treat HRN gpt delta mice and control littermates.gpt gene mutant frequencies (MFs) in liver and lungs were detected and mutational spectra were analysed.Pharmacokinetics analysis was performed and tissue level of BaP and NNK was determined by high-performance liquid chromatography (HPLC) with fluorescence detection and liquid chromatography-tandem mass spectrometry respectively.The NNK-induced MFs were reduced to the level of spontaneous MFs in the liver but a more than 3 times increase in the lungs in HRN gpt delta mice compared with control littermates was observed.The BaP-induced MFs were increased in both liver and lungs in HRN gpt delta mice.Pharmacokinetic analyses were perfromed from blood in treated animals and a reduced clearance of NNK and BaP in HRN gpt delta mice was observed,meanwhile, elevated concentrations of both of the compounds were detected in lung and liver tissues of HRN mice.For NNK, our findings suggest that hepatic P450 plays a major role in the systemic clearance of NNK rather than activation, thereby protecting the lung against NNK-induced carcinogenesis.Moreover, P450 is the only enzyme responsible for NNK activation in the liver.Although hepatic P450 is responsible also for the detoxification of BaP, however, there must exist some other metabolic activation enzymes in the liver by a CYP-indepndent mechanism which may also be involved in BaP-mediated carcinogenesis.