Vegetable consumption, specifically cruciferous vegetable consumption, has long been linked to decreased cancer-risk. Unique to cruciferous vegetables is high glucosinolate content. Glucosinolates are sulfur containing plant defense compounds that are hydrolyzed into isothiocyanates (ITCs) and indoles by the plant enzyme myrosinase upon damage to the plant tissue. The main chemopreventive agent from crucifers are ITCs. ITCs have been indicated as chemopreventive against lung, colorectal and breast cancer. For lung cancer, it has been shown in Chinese populations (described below in section C2) that ITCs decrease the risk of lung cancer in smokers. Our studies will help determine the mechanisms by which this occurs and what factors may modify this relationship. ITCs are thought to increase the excretion of the highly carcinogenic nitrosamine 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK), which is present only in cigarette smoke. Once inhaled, NNK is converted to 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanol (NNAL) by carbonyl reduction. Both NNK and NNAL are DNA-adduct forming compounds. However, NNAL can be conjugated by UDP-glucuronosyltransferases (UGTs) to form NNAL-gluc, which increases solubility and therefore urinary excretion. UGTs 2B10 and 2B17 have been shown to be responsible for most of the NNAL glucuronidation. Both NNAL and NNAL-gluc can be measured in the urine of smokers, neither compound is present in nonsmokers who are not exposed to environmental tobacco smoke. ITCs can also be measured in urine after consumption of cruciferous vegetables and has been shown to be dose dependent to dietary intake of these vegetables. The literature in this area is further described below under the chemoprevention section. The overall hypothesis is that the relationship between ITC intake and lung cancer risk is due to a direct effect of ITC on NNAL metabolism in smokers. We will address this issue by conducting a study to measure urinary ITC levels in a biracial American population of 161 smokers from NY that have already been measured for urinary NNAL levels.
|Modesto, Jennifer L; Hull, Anna; Angstadt, Andrea Y et al. (2015) NNK reduction pathway gene polymorphisms and risk of lung cancer. Mol Carcinog 54 Suppl 1:E94-E102|