Cancer Letters

Cancer Letters

Volume 187, Issues 1–2, 10 December 2002, Pages 95-101
Cancer Letters

Microsomal epoxide hydrolase and glutathione S-transferase polymorphisms in relation to laryngeal carcinoma risk

https://doi.org/10.1016/S0304-3835(02)00406-8Get rights and content

Abstract

Two polymorphic sites of the microsomal epoxide hydrolase gene (EPHX1, 113Tyr→113His, 139His→139Arg) and four glutathione S-transferase genes (GSTM1, GSTM3, GSTP1, GSTT1) were genotyped in a group of patients with larynx cancer (N=204) and in a group of healthy controls (N=203), all Spanish caucasians. After adjusting for gender, age, and tobacco smoking, none of the polymorphisms alone were found to be associated with larynx cancer risk. The analysis of EPHX1/GST combinations, however, showed a significant over-representation of patients with a combination of 113Tyr/113Tyr EPHX1 and 105Ile/105Ile GSTP1 (adjusted odds ratio (OR): 1.95; 95% confidence interval (CI): 1.02–3.78). The calculation of the predicted epoxide hydrolase (EH) activity also showed an increased risk for the individuals with both predicted high activity EH and 105Ile/105Ile GSTP1 (OR: 2.90; 95% CI: 1.10–7.67). These results on larynx cancer tend to confirm a former study on lung cancer (Cancer Lett. 173 (2001) 155) suggesting the existence of an interaction between variants of EH and GSTpi, both enzymes being involved in the metabolism of aromatic hydrocarbons, that may increase susceptibility to tobacco-related cancers.

Introduction

Several polymorphic genes, encoding for enzymes involved in the biotransformation of carcinogens, have been studied as possible cancer risk modifiers. Most tobacco pro-carcinogens, as benzo[a]pyrene (BP), are activated by phase I enzymes to ultimate reactive intermediates which bind to DNA and induce mutations in critical hotspots [1]. Therefore, genetic variability in phase I activation and phase II detoxication has been postulated as a possible determinant of cancer susceptibility [2]. Cancers of the upper aerodigestive tract, as laryngeal carcinoma, strongly associated with tobacco smoke, alcohol and other possible exogenous risk factors, are currently investigated in relation to enzymes involved in bioactivation/deactivation reactions as microsomal epoxide hydrolase (EH, E.C. 3.3.2.3) and glutathione-S transferases (GSTs, EC 2.5.1.18).

Both EH and GSTs are enzymes involved in the metabolism of reactive intermediates, notably polycyclic aromatic hydrocarbons (PAHs) of tobacco smoke. EH is generally viewed as an inactivation enzyme since it catalyses the conversion of highly reactive epoxides to dihydrodiols [3]. However, some dihydrodiols can be subsequently metabolized to highly mutagenic polycyclic hydrocarbon diol epoxides. Therefore, EH can play a dual role in the activation/detoxication of procarcinogens. The EH enzyme is encoded by a single gene (EPHX1) in 1p11-qter [4], [5] and two polymorphic sites have been reported within the coding region. An exon 3 polymorphism results in a Tyr→His substitution in residue 113 and an exon 4 polymorphic site results in a 139 His→Arg substitution [6], [7]. According to in vitro studies, these exon 3 and 4 substitutions may, respectively, decrease and increase EH activity in tissues [8].

Several GST genes are also polymorphic in humans [9], [10]. The GSTM1 gene (1p13), encoding for a mu-GST isoenzyme, is known to exist in two allelic forms (GSTM1*A/GSTM1*B) and is deleted (GSTM1*0/0) in about 50% of caucasian individuals. Another GSTM gene of the same cluster (GSTM3) presents an intronic polymorphic site (3 bp deletion in intron 6), while GSTT1 (22q 11.2), encoding for a theta-GST isoenzyme, is also frequently deleted (GSTT1*0) among caucasians. GSTP1 (11q3) encodes for a pi-GST isoenzyme heavily expressed in the digestive and respiratory epithelium, is found in humans in two allelic forms (GSTP1*A/GSTP1*B) with an A→G substitution at exon 5 causing an 105Ile→105Val replacement within the active site of the protein [11], [12].

Most of the GST polymorphisms have been investigated in relation to various types of tobacco-related cancers as lung and upper aerodigestive tract tumours, without definitive conclusions [13]. Regarding larynx cancer, possible associations with either GSTM1 null, GSTT1 null, GSTM3 or GSTP1 have been reported [14], [15], [16], [17], [18], [19], [20]. The role of the EH polymorphisms on cancer risk is also controversial, with discrepant results being found in the literature [21], [22], [23], [24], [25], [26]. In a recent study, however, we found an interaction between EH and GSTP1 that increased lung cancer risk among Spanish caucasians [27]. This suggested the possibility of a combined role of two or more genes on BP activation/deactivation ratio. In the present study, we have addressed this possibility by studying the risk associated with the polymorphisms of EH and GST alone and in combination, on squamous cell carcinoma of the larynx.

Section snippets

Material and methods

The study involved a group of 204 patients with larynx cancer and a control group of 203 healthy volunteers. All cases and controls were Spanish caucasians, as judged by their names and places of birth, with residence in the area of Barcelona (Catalonia).

The cases were patients diagnosed of squamous cell carcinoma (SCC) of the larynx (126 glottic, 78 supraglottic) who underwent partial or total laryngectomy at the ‘Hospital Clı́nic’ or ‘Hospital Prı́nceps d'Espanya’, University of Barcelona,

Results

The distribution of the GSTM1null, GSTM1A/B, GSTT1, GSTP1 and GSTM3 among the controls and the patients can be found in Table 1. We found among the healthy controls, GST frequencies that were, in most cases, in accordance with other studies performed among European caucasians. The two GST gene deletions (GSTM1*0/0 and GSTT1*0/0) showed high frequency among the control group. GSTM1 was found to be deleted in nearly 50% of individuals which is in close agreement with the GSTM1*0/0 frequency among

Discussion

Our results among Spanish caucasians do not support the hypothesis that any of the single polymorphisms studied is associated with laryngeal cancer. In some cases, this conclusion is in contradiction with other phenotyping or genotyping studies that reported increased risks associated with some of the GST variants [17]. Most notably, we did not find any over-representation of patients with the GSTM1 null genotype as had been reported by some early studies among caucasians [18]. A similar trend,

Acknowledgements

This study was supported by Spanish ‘Fondo de Investigación Sanitaria’ (grant no. 00/0504)

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