Genetic polymorphisms in CYP1B1, GSTA1, NQO1 and NAT2 and the risk of lung cancer
Introduction
Tobacco smoking is the strongest known risk factor for lung cancer. Carcinogens present in tobacco smoke, such as polycyclic aromatic hydrocarbons (PAHs), quinones and arylamines, are mainly metabolised by phase I and II enzymes and polymorphisms in genes coding for these enzymes have been studied as possible modulators of risk for lung cancer.
A highly studied phase I gene is cytochrome P450 1A1 (CYP1A1). However, CYP1A1 is uncommonly detected in lung tissue at both mRNA and protein level [1] and no major effects on enzyme activity have been associated to any variant alleles in CYP1A1 [2]. Another phase I enzyme, CYP1B1, has been found to activate several PAHs found in tobacco smoke, including PAHs previously assumed to be activated mainly by CYP1A1 [3]. Unlike CYP1A1, CYP1B1 is expressed in human lung tissue [1]. In a polymorphism in CYP1B1 at codon 432 (Val→Leu), the variant allele has been associated with a slightly increase in the catalytic activation of some PAHs [3]. Only one case-control study known to us has investigated the relationship between lung cancer and this CYP1B1 polymorphism and found no association [4].
Glutathione S-transferases (GSTs) constitute a multigene family of phase II enzymes that deactivates many carcinogenic substrates. Several polymorphisms have been identified in GSTs. We have previously found that carriers of the GSTT1 null genotype were at significantly higher risk of lung cancer than individuals with GSTT1 present, whereas we found no effect of polymorphisms in GSTM1 or GSTP1 [5]. GSTA1/A2 and GSTP1 are the most abundant GSTs in the human lung [6]. A polymorphism in the proximal promoter of GSTA1, in which the variant allele is associated with decreased expression of GSTA1 [7], has been found associated with colorectal cancer [8]. We are not aware of any other studies that have investigated the relationship between this polymorphism and the risk of lung cancer. Another phase II enzyme, NAD(P)H quinone oxidoreductase (NQO1), is a two-electron reductase that depending of the substrate can either bioactivate or detoxify quinones. A polymorphism in codon 187 in NQO1 (Ser→Pro) has been associated with low activity of the enzyme [9]. The effect of the NQO1 genotype is ambiguous and has been associated with both higher [10] and a lower [11] risk of lung cancer. Arylamines are potential carcinogens that depending of the type can be either bioactivated or detoxified by the phase II enzyme NAT2. NAT2 is expressed in the human lung, although at low concentrations [12]. Polymorphisms in NAT2 result in NAT2 enzymes with either slow or fast acetylation capacity. The NAT2 slow acetylator genotype has been found to be a risk factor for lung cancer in non-smokers but protective among heavy smokers [13], [14], [15].
In the present study, we wanted to examine the relationship between polymorphisms in the metabolism genes CYP1B1, GSTA1, NQO1 and NAT2 and the risk of lung cancer in a population-based case-cohort study, matched on duration of smoking. We have previously examined relationships between polymorphisms in GSTT1, GSTM1 and GSTP1 and risk of lung cancer in the same study population [5].
Section snippets
Study population
Diet, cancer and health (DCH) is a Danish prospective follow-up study. Invited to participate were 160,725 individuals aged 50–64 years, of whom 57,053 individuals with no previous cancer diagnosis were recruited [16]. At enrolment (1993–1997), detailed information on diet, smoking habits, lifestyle, weight, height, reproduction, medical treatment and other socio-economic characteristics and environmental exposures were collected. Moreover, blood, urine and fat tissue was sampled and stored in
Results
Cases and sub-cohort members were similarly distributed with respect to age, smoking status and smoking duration at inclusion into the cohort (Table 1), and also with respect to gender with 56% men among the cases and 55% men among the sub-cohort. We found that the averages in smoking intensity in present smokers between the cases (21±11 g tobacco/day) and the sub-cohort (19±12 g tobacco/day) was similar. The genotype distribution in the control group was in Hardy–Weinberg equilibrium for CYP1B1,
Discussion
We found that overall the risk of lung cancer was not significantly associated with polymorphisms in either CYP1B1, GSTA1, NQO1 or NAT2, but that subjects smoking 1–20 cigarettes per day and carrying the NAT2 fast acetylating genotype were at lower risk of lung cancer than the slow acetylators, whereas for heavy smokers the fast acetylating genotype was not associated with a lowering in risk.
Analyses of the present dataset involved a large number of statistical tests, and we can, therefore, not
References (30)
- et al.
The role of human glutathione S-transferases (hGSTs) in the detoxification of the food-derived carcinogen metabolite N-acetoxy-PhIP, and the effect of a polymorphism in hGSTA1 on colorectal cancer risk
Mutat. Res.
(2001) - et al.
Polymorphisms in the NAD(P)H: quinone oxidoreductase gene and small cell lung cancer risk in a UK population
Lung Cancer
(2001) - et al.
Analysis of case-cohort designs
J. Clin. Epidemiol.
(1999) - et al.
Phase I and II carcinogen metabolism gene expression in human lung tissue and tumors
Clin. Cancer Res.
(2003) Cytochrome P450 gene polymorphism and cancer
Curr. Drug Metab.
(2004)- et al.
Catalytic properties of polymorphic human cytochrome P450 1B1 variants
Carcinogenesis
(1999) - et al.
Association of CYP1B1 genetic polymorphism with incidence to breast and lung cancer
Pharmacogenetics
(2000) - et al.
Glutathione S-transferase T1 null-genotype is associated with an increased risk of lung cancer
Int. J. Cancer
(2004) - et al.
Immunohistochemical localization of glutathione S-transferases in human lung
Cancer Res.
(1993) - et al.
Effect of polymorphism in the human glutathione S-transferase A1 promoter on hepatic GSTA1 and GSTA2 expression
Pharmacogenetics
(2001)