Effects of citrus phytochemicals on liver and lung cytochrome p450 activity and on the in vitro metabolism of the tobacco-specific nitrosamine NNK

NNK is a potent environmental carcinogen to which both smokes and nonsmoker s are exposed. The response to NNK may be affected by factors including nut rition. We investigated the effects of five citrus phytochemicals on the in vitro metabolism of the tobacco-specific nitrosamine NNK and on the dealky lation of methoxyresorufin (MROD) and pentoxyresorufin (PROD) in liver and lung microsomes of the Syrian golden hamster: In the NNK metabolism experim ents in vitro incubations contained 3 mu Ci [5-H-3] NNK, 0.5 mg microsomal protein and 0.5 mu mole of the citrus phytochemical diosmin, naringin, nari ngenin, quercetin or rutin. In the dealkylation studies incubations contain ed 0.5 muM methoxyresorufin or pentoxyresorufin, 0.5 mg microsomal protein and 0.5 mu mole of citrus phytochemical. The major NNK metabolism pathway i n hamster liver microsomes was NNK-reduction while in lung microsomes it wa s a-hydroxylation. The alpha -hydroxylation pathway produces metabolic prod ucts that methylate and pyridyloxobutylate DNA. Naringenin, a metabolite of naringin, and quercetin were the most potent inhibitors of alpha -hydroxyl ation of NNK in both liver and lung microsomes. This inhibition correlated with a potent inhibition of MROD and PROD activity in liver but not in lung microsomes. The metabolic activation of NNK is associated with cytochrome P450 isoforms 1A1, 1A2 2B1, 2D6 and 2E1. Our results suggest that naringeni n and quercetin fi om citrus fruits inhibit the activity of cytochrome P450 (CYP) isoforms that activate NNK and may afford protection against NNK-ind uced carcinogenesis.