ArticlesIsothiocyanates, glutathione S-transferase M1 and T1 polymorphisms, and lung-cancer risk: a prospective study of men in Shanghai, China
Introduction
Many experimental studies in animals show that isothiocyanates inhibit lung carcinogenesis.1, 2 The main mechanisms proposed are interference with metabolic activation of procarcinogens in tobacco smoke by cytochrome P450s and enhancement of the detoxification of these activated carcinogens by glutathione S-transferases (GST).2 Isothiocyanates may also inhibit carcinogenesis by inhibition of apoptosis3 or protection against oxidative damage.4, 5
Cruciferous vegetables (family name Cruciferae or Brassicaceae), primarily those of the Brassica genus (including broccoli, cabbage, and bok choi) are the main dietary sources of the glucosinolate precursors of isothiocyanates. Damage to plant cells, such as from cutting and chewing, releases myrosinase that hydrolyses glucosinolates to isothiocyanates. Epidemiological studies suggest that intake of such vegetables reduces the risk of lung cancer.6 However, there are no studies with biological measurements of isothiocyanates in relation to the risk of lung or other cancers to provide direct evidence that isothiocyanates, as opposed to other compounds in these vegetables, are chemopreventive in human beings. A urinary biomarker of total dietary intake of isothiocyanates suitable for use on stored samples has been developed and validated in a controlled feeding experiment.7 The biomarker correlates well with dietary intake in a Chinese population with frequent consumption of isothiocyanate-rich vegetables.8
GSTs are a family that detoxify reactive electrophiles such as epoxides.9 GSTM1 detoxifies the ultimate carcinogen metabolite of benzo[a]pyrene, a polyaromatic hydrocarbon in tobacco smoke.9 Common homozygous deletion polymorphisms of GSTM1 and GSTT1, abolish the respective enzyme activities and have been associated with modest increase in lung cancer in some but not all studies.10 However, conjugation with glutathione catalysed by the GSTs promotes the elimination not only of carcinogens but also of anticarcinogenic substances, such as isothiocyanates,11 and thus could decrease isothiocyanate chemopreventive effects.
We examined the relation between a urinary biomarker of total isothiocyanate intake and lung-cancer risk in a prospective cohort of men in Shanghai, China—a population with frequent consumption of vegetables rich in isothiocyanate precursors. We also investigated whether generic polymorphisms of GSTM1 and GSTT1 modify the effect of isothiocyanate concentrations on lung-cancer risk.
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Study individuals
Study individuals were drawn from a prospective study of men in Shanghai, China.12, 13 In brief, between Jan 1, 1986, and Sept 30, 1989, all male residents of four, small, geographically defined communities in Shanghai, who were aged 45–64 years and had no history of cancer, were invited to participate in an epidemiological study. At enrolment, individuals provided 10 mL blood and one single-void urine sample. Samples were stored at −20°C. Each individual was interviewed in person with a
Results
The mean age at interview was identical for the case and control groups—58·8 years (SD 4·8) for each. At interview, 47·5% of controls and 81·5% of cases reported being current smokers. Past smoking was uncommon and equally distributed between cases and controls (8·2%). Among smokers, the mean number of cigarettes smoked per day was 21 (8) for cases and 15 (8) for controls.
Among all individuals with detectable isothiocyanate, the range was 0·04–77·7 μmol/mg of creatinine, with a median of 1·71
Discussion
In our prospective study, individuals with detectable concentrations of isothiocyanates in the urine were at decreased risk of lung cancer. The reduction in risk of lung cancer associated with isothiocyanates was greatest for individuals with homozygous deletions of GSTM1 and GSTT1. GSTM1 and GSTT1 are genes that code for enzymes catalysing conjugation and hence elimination of chemopreventive isothiocyanates as well as carcinogens, such as benzo[a]pyrene, in tobacco smoke. Conversely, among
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