Abstract
Nobiletin, a major component of citrus polymethoxyflavones, possesses anticancer, antiviral and anti-inflammatory activities. To evaluate the chemopreventive potential against lung cancer induced by cigarette smoke, we examined suppressive effects of nobiletin against genotoxicity induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the most carcinogenic tobacco-specific nitrosamine, in the lung of gpt delta transgenic mice. Male and female gpt delta mice were fed nobiletin at a dose of 100 or 500 ppm in diet for seven days and treated with NNK at a dose of 2 mg/mouse/day, i.p. for four consecutive days. Dietary administration of nobiletin continued at the doses during the NNK treatments and in the following period before sacrifice at day 38. NNK treatments enhanced the gpt mutant frequency (MF) in the lung 19- and 9-fold, respectively, over the values of untreated female and male mice. Interestingly, nobiletin reduced the NNK-induced MFs by 25-45% in both sexes and the reduction at a dose of 100 ppm in females and 500 ppm in males was statistically significant (P<0.05). To further characterize the suppressive effects, we conducted bacterial mutation assay with Salmonella typhimurium YG7108 to examine whether nobiletin inhibits S9-mediated genotoxicity of NNK. Nobiletin as well as 8-methoxypsoralen, an inhibitor of CYP2A, reduced the genotoxicity of NNK by more than 50%. These results suggest that nobiletin may be chemopreventive against NNK-induced lung cancer and also that the chemopreventive efficacy may be due to inhibition of certain CYP enzymes involved in the metabolic activation of NNK.
