title: Effects of dietary sinigrin or indole-3-carbinol on O6-methylguanine-DNA-transmethylase activity and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced DNA methylation and tumorigenicity in F344 rats.
abstract: The effects of dietary sinigrin and indole-3-carbinol (I3C) on DNA methylation and O6-methylguanine--DNA-transmethylase activity, factors which may be of importance in the induction of tumorigenicity by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), were investigated. Additionally, the effects of dietary sinigrin on NNK tumorigenicity were assessed in a two-year bioassay in F344 rats. DNA methylation in target tissues of NNK tumorigenesis was examined in F344 rats administered [3H-CH3]NNK (0.6 mg/kg, four doses) s.c. and fed control or experimental diets for two weeks. Dietary sinigrin at a concentration of 3 mumol/g diet decreased 7-methylguanine formation in hepatic DNA, but had no effect on 7-methylguanine levels of lung or nasal mucosa DNA. Dietary I3C at a concentration of 30 mumol/g diet increased 7-methylguanine levels in hepatic DNA, but decreased DNA methylation in lung and nasal mucosa. No effects on O6-methylguanine--DNA-transmethylase activity were observed in tissue extracts derived from the livers, lungs and nasal mucosae of rats fed diets containing sinigrin or I3C. These results suggested that dietary sinigrin might reduce the incidence of NNK-induced hepatic tumors with no effect on NNK tumorigenesis of the lung and nasal cavity, whereas I3C might increase hepatic tumor incidence and reduce NNK tumorigenesis of the lung and nasal cavity. The bioassay results showed that dietary sinigrin had no effect on NNK tumorigenesis in these target tissues. However, dietary sinigrin plus NNK resulted in a significant incidence of pancreatic tumors, a rare occurrence in F344 rats. While the results from DNA methylation studies are in agreement with the bioassay data for lung and nasal cavity, the absence of any inhibitory effect of dietary sinigrin on NNK hepatic tumorigenesis indicates that factors other than DNA methylation and O6-methylguanine repair should be considered in assessing the effects of dietary compounds on NNK hepatic tumorigenesis. The contrary effects on NNK-induced hepatic DNA methylation by sinigrin and I3C, two major components of cruciferous vegetables, demonstrate the complexities of dietary modulation of carcinogenesis.
authors.affiliation: Division of Chemical Carcinogenesis, American Health Foundation, Valhalla, NY 10595.
authors.forename: M A
authors.initials: MA
authors.lastname: Morse
authors.forename: C X
authors.initials: CX
authors.lastname: Wang
authors.forename: S G
authors.initials: SG
authors.lastname: Amin
authors.forename: S S
authors.initials: SS
authors.lastname: Hecht
authors.forename: F L
authors.initials: FL
authors.lastname: Chung
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004247:DNA / Q000378:metabolism*; D004032:Diet; D005961:Glucosinolates / Q000008:administration & dosage / Q000494:pharmacology*; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000139:chemically induced; D008175:Lung Neoplasms / Q000139:chemically induced; D008297:Male; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000473:pathology*; D009602:Nitrosamines / Q000378:metabolism / Q000633:toxicity*; D009669:Nose Neoplasms / Q000139:chemically induced; D019853:O(6)-Methylguanine-DNA Methyltransferase; D010190:Pancreatic Neoplasms / Q000139:chemically induced; D051381:Rats; D011916:Rats, Inbred F344; D013865:Thioglycosides / Q000494:pharmacology*
chemical_list: D002273:Carcinogens; D005961:Glucosinolates; D007211:Indoles; D009602:Nitrosamines; D013865:Thioglycosides; C010330:sinigrin; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D004247:DNA; C016517:indole-3-carbinol; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase