Chemopreventive Effects of Nobiletin against Genotoxicity Induced by 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the Lung of gpt delta Transgenic Mice

Abstract

Nobiletin, a major component of citrus polymethoxy‰a-vones, possesses anticancer, antiviral and anti-in‰amma-tory activities. To evaluate the chemopreventive potential against lung cancer induced by cigarette smoke, we examined suppressive eŠects of nobiletin against genotoxicity induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the most carcinogenic tobacco-speciˆc 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 sacriˆce 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 signiˆcant (Pº0.05). To further characterize the suppressive eŠects, 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 e‹cacy may be due to inhibition of certain CYP enzymes involved in the metabolic activation of NNK.

Dietary Phytochemicals as Potential Chemopreventive Agents against Tobacco-Induced Lung Carcinogenesis

“…Nobiletin, a major component of citrus polymethoxy flavones, has anti-cancer effects [ 108 ]. Nobiletin inhibited CYP enzymes involved in the metabolic activation for preventing lung cancer [ 66 ]. In NNK-treated mice, oral nobiletin significantly suppressed lung tumorigenesis and decreased tumor volume [ 67 ].…”

Multifunctional role of Nobiletin in cancer chemoprevention

“…Nobiletin has been shown to reduce the genotoxicity of NNK by inhibiting CYP2A enzyme in the lung of gpt delta transgenic mice. It is important to note that NKK is metabolically activated by CYP2A enzyme to the genotoxic metabolites (69). Another study has shown that nobiletin can downregulate the mutagenic potential of food derived environmental pro-carcinogen PhIP by inhibiting CYP1A2 that is involved in the bioactivation of PhIP (70).…”