Flavonoids suppresses the enhancing effect of beta-carotene on DNA damage induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A549 cells.
This study investigated the individual and combined effects of beta-carotene with a common flavonoid (naringin, quercetin or rutin) on DNA damage induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent tobacco-related carcinogen in human. A human lung cancer cell line, A549, was pre-incubated with beta-carotene, a flavonoid, or both for 1h followed by incubation with NNK for 4 h. Then, we determined DNA strand breaks and the level of 7-methylguanine (7-mGua), a product of NNK metabolism by cytochrome P450 (CYP). We showed that beta-carotene at 20 microM significantly enhanced NNK-induced DNA strand breaks and 7-mGua levels by 90% (p < 0.05) and 70% (p < 0.05), respectively, and that the effect of beta-carotene was associated with an increased metabolism of NNK by CYP because the concomitant addition of 1-aminobenzotriazole, a CYP inhibitor, with beta-carotene to cells strongly inhibited NNK-induced DNA strand breaks. In contrast to beta-carotene, incubation of cells with naringin, quercetin or rutin added at 23 microM led to significant inhibition of NNK-induced DNA strand breaks, and the effect was in the order of quercetin > naringin > rutin. However, these flavonoids did not significantly affect the level of 7-mGua induced by NNK. Co-incubation of beta-carotene with any of these flavonoids significantly inhibited the enhancing effect of beta-carotene on NNK-induced DNA strand breaks; the effects of flavonoids were dose-dependent and were also in the order of quercetin > naringin > rutin. Co-incubation of beta-carotene with any of these flavonoids also significantly inhibited the loss of beta-carotene incorporated into the cells, and the effects of the flavonoids were also in the order of quercetin > naringin > rutin. The protective effects of these flavonoids may be attributed to their antioxidant activities because they significantly decreased intracellular ROS, and the effects were also in the order of quercetin > naringin > rutin. These in vitro results suggest that a combination of beta-carotene with naringin, rutin, or quercetin may increase the safety of beta-carotene.
Institute of Nutritional Science, Chung Shan Medical University, Taichung, Taiwan, ROC.
Shu-Lan
SL
Yeh
Wei-Yu
WY
Wang
Chin-Shiu
CS
Huang
Miao-Lin
ML
Hu
D004249:DNA Damage / Q000187:drug effects*; D004336:Drug Antagonism; D004338:Drug Combinations; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D044950:Flavanones / Q000378:metabolism / Q000494:pharmacology; D005419:Flavonoids / Q000378:metabolism / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D009602:Nitrosamines / Q000378:metabolism / Q000633:toxicity*; D011794:Quercetin / Q000378:metabolism / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D020545:Respiratory Mucosa; D012431:Rutin / Q000378:metabolism / Q000494:pharmacology; D019207:beta Carotene / Q000378:metabolism / Q000494:pharmacology*
D004338:Drug Combinations; D044950:Flavanones; D005419:Flavonoids; D009602:Nitrosamines; D017382:Reactive Oxygen Species; D019207:beta Carotene; D012431:Rutin; D006147:Guanine; C008450:7-methylguanine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D011794:Quercetin; C005274:naringin