The role of glucosinolates in cruciferous vegetables as well as the derived isothiocyanates and indoles as modifiers of metabolic activation and tumorigenesis of N-nitrosodimethylamine (NDMA) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) will be assessed. The effects of compounds on levels of 7-methylguanine (7-mG) and O6-methylguanine (O6-mG) induced by NDMA and NNK in tissue DNA; and on the rate of removal of 06-mG will be determined. This study is important and has practical significance in view of the extensive human exposure to glucosinolates through vegetable consumption and to NDMA and NNK through tobacco usage. Our preliminary studies showed that pretreatment of rats with non-toxic doses of isothiocyanates and indoles profoundly affects the metabolic Alpha-hydroxylation of various nitrosamines. Whereas isothiocyanates strongly inhibited Alpha-hydroxylation, indoles induced it. The opposing effects of isothiocyanates and indoles are of importance because both compounds occur in cruciferous vegetables in significant amounts. We have also shown that sinigrin, a glucosinolate precursor of allyl isothiocyanate, inhibited both in vitro Alpha-hydroxylation and in vivo DNA methylation by NDMA and NNK. These results prompted us to extend our study to four commonly occurring glucosinolates to determine their effects on the kinetics of DNA methylation by NDMA and NNK in the target and non-target tissues as well as on the activity of the DNA repair enzymes, e.g. O6-mG-DNA transmethylase. The glucosinolates included are sinigrin, glucoiberin, gluconasturtiin, and glucobrassicin. Furthermore, the in vivo conversion of glucosinolates to isothiocyanates or indoles will be investigated. These studies should provide practical information regarding the potential role of glucosinolates and their related compounds in modification of NDMA and NNK carcinogenesis.
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| Morse, M A; LaGreca, S D; Amin, S G et al. (1990) Effects of indole-3-carbinol on lung tumorigenesis and DNA methylation induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and on the metabolism and disposition of NNK in A/J mice. Cancer Res 50:2613-7 |
