Induction of N-nitrosodimethylamine metabolism in liver and lung by in vivo pyridine treatments of rabbits

Abstract.

N-Nitrosodimethylamine is a procarcinogen that is activated by cytochrome P450 dependent N-nitrosodimethylamine N-demethylase to labile α-carbon hydroxylated products further resulting in active methylating agents. In vivo intraperitoneal administration of pyridine to rabbits significantly increased N-nitrosodimethylamine N-demethylase activity by 6.9- and 5.2-fold in liver and lung microsomes, respectively. Although, p-nitrophenol hydroxylase and aniline 4-hydroxylase activities were markedly enhanced by pyridine treatment in liver about 4.4- and 5.8-fold, respectively, no change was observed in the activities of these enzymes in lung microsomes. Pyridine treatment also elevated P450 contents of liver and lung by 2.04- and 1.4-fold, respectively. SDS-PAGE of pyridine-induced liver microsomes revealed a protein band of enhanced intensity having M_r of 51,000 migrating in the region of cytochrome P4502E1. The results obtained in this study demonstrated for the first time, a significant 5.2-fold induction of NDMA N-demethylase activity in the rabbit lung over the controls. Pyridine is readily absorbed by inhalation and is a constituent of tobacco and tobacco smoke. Thus induction of NDMA N-demethylase suggests that in the lung, as in the liver, pyridine may stimulate the metabolic activation of this nitrosamine significantly.