The Modulation of Lung Cancer Risk by Glutathione S-Transferase M1-Diet Interactions

Abstract

Fruits and vegetables are considered to be protective against lung cancer, as is shown in epidemiological studies. They contain antioxidants which protect against oxidative DNA damage and induce detoxifying enzymes. Isothiocyanates, present in cruciferous vegetables, have chemo-preventive abilities by inhibition of phase I enzymes and induction of phase II enzymes. A lack of phase II glutathione S-transferases (GSTs) results in a higher lung cancer risk, since reactive carcinogen metabolites are no longer detoxified. These GST enzymes are also responsible for the elimination of isothiocyanates. A homozygous deletion in GST genes can therefore result in a higher concentration or longer exposure to the protective isothiocyanates, while antioxidants might compensate this loss by induction of other phase II enzymes. It has been suggested that people lacking certain glutathione S-transferase genes benefit more from the chemo-protective abilities of vegetables. We evaluated the modulating effects of the GSTM1 genotype on the protective abilities of vegetable consumption against lung cancer risk by assessing epidemiological and molecular epidemiological studies. Nine out of thirteen epidemiological studies, report a lowered lung cancer risk for subjects with high vegetable intake and a homozygous deletion of the GSTM1 gene, compared to subjects without this deletion. In the molecular epidemiological studies there is some discrepancy between results of studies measuring bulky lesions (e.g. DNA adducts) and oxidative parameters as biomarkers of lung cancer risk, possibly because of different mechanistic origins. Overall, eight of the thirteen molecular epidemiological studies report an inverse association between high antioxidant levels (present in vegetables) and molecular damage which is only seen in GSTM1-null subjects. From these results we can conclude that the GSTM1-null genotype in combination with certain constituents of vegetables have a probable protective effect against lung cancer.