Roles of Pulmonary and Hepatic Cytochrome P450 in 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK)‐Induced Lung Tumorigenesis in Mice

Abstract

An important issue in the mechanisms of xenobiotic metabolism and chemical carcinogenesis is whether microsomal cytochrome P450 (P450) enzymes of various extrahepatic target tissues are responsible for the tissue-selective tumorigenicity of chemical compounds. To answer this question, we conducted in vivo studies using mice with tissue-selective deletion of the NADPH-cytochrome P450 reductase (Cpr or Por) gene, which is essential for the function of all microsomal P450 enzymes. In the present study, transgenic mice with lung-specific deletion of the Cpr gene, named as lung-Cpr-null mice, were generated. Deletion of Cpr in the lung was limited to the Clara cells, as indicated by immunohistochemical analysis, and to type II alveolar epithelial cells, as demonstrated by PCR analysis of isolated lung cells. The in vitro activity of whole lung microsomal preparations toward NNK, one of the most potent carcinogens in tobacco smoke, was only about 25% lower in the lung-Cpr-null mice than in wild-type control mice. However, the multiplicity of NNK-induced lung tumors was significantly reduced in the lung-Cpr-null mice, compared to the tumor multiplicity in control littermates. In contrast, the tumor multiplicity was significantly higher in mice with liver-specific deletion of the Cpr gene than in control littermates. These results indicate that metabolic activation by lung microsomal P450 plays a dominant role in NNK-induced lung tumorigenesis. (Supported in part by NIH grant CA092596)