Microsomal epoxide hydrolase gene polymorphism and susceptibility to colon cancer

Abstract

The colon is subject to oxidative and free radical damage by both products of endogenous metabolism and bacterial fermentation within the gut lumen. These injurious stimuli may cause cell damage or cell death or even lead to mutations, resulting in tumour initiation and progression. Colon cancer is a common disease, with the highest incidence in developed countries. The aetiology is unknown, but in addition to diet and cigarette smoking (Giovannucci and Willett, 1994) there is a complex polygenic background that determines individual susceptibility to disease. There is currently much interest in the roles of oncogenes, tumoursuppressor genes and mismatch repair enzymes in colon cancer (Tomlinson et al, 1997). In addition, interindividual variation in the ability to dispose of reactive xenobiotics catalysed by glutathione S-transferases GST-M1 and GST-T1 has been investigated (Lang et al, 1986;Strange et al, 1991;Zhong et al, 1993;Chenevix-Trench et al, 1995). However, results from a number of studies show only weak and inconsistent associations with disease susceptibility. N-acetyltransferase 2 (NAT-2) polymorphism may be implicated in susceptibility to colon cancer (Lang et al, 1986;Wohlleb et al, 1990;Illett et al, 1994;Probst-Hensch et al, 1995), but there is evidence that its relationship may be by linkage with other genes rather than causally (Hubbard et al, 1997).We have used a polymerase chain reaction (PCR) strategy to investigate whether polymorphisms in the microsomal epoxide hydrolase gene (mEPHX) (Hassett et al, 1994) have any relationship to colon cancer. The enzyme is expressed in many tissues, including colon and liver. Polymorphisms of mEPHX may have functional significance. There is variation in exon 3, where a T to C alteration changes tyrosine residue 113 to histidine and is associated with lower enzyme activity when expressed in vitro. By contrast, A to G transition in exon 4 changes histidine residue 139 to arginine and produces increased enzyme activity. The effect of combining the alleles has not been established. The activity of mEPHX varies more than 50-fold in Caucasians (Omiecinski et al, 1993). This variation of activity is, thus, due to a combination of genetic polymorphism, transcriptional and post-transcriptional control of gene expression. MATERIALS AND METHODS Controls and cancer casesControl blood samples (n = 203) were obtained anonymously from the Scottish National Blood Transfusion Service. These were Caucasian individuals aged between 18 and 65 years with equal sex distribution. This group has been previously described (Cantlay et al, 1994) and was drawn from the same geographical area as the cancer study group. The presence of colorectal neoplasia was not specifically excluded, but all patients were healthy. Peripheral blood from patients with colorectal cancer was collected from a consecutive series of operable colorectal cancer cases after surgery in four local hospitals between 1988 and 1993 (n = 101). Cancer patient dataCancer diagnosis was confirmed histopathologically...

Epoxide hydrolases: biochemistry and molecular biology

“…Polymorphisms in mEH too may lead to differences in host-mediated bioactivation of procarcinogens resulting in differential susceptibility to cancers of various tissues. Numerous human epidemiological studies have examined the role of the polymorphism in mEH and tumor formation [124][125][126][127][128]. These data suggest that mEH genotype is associated with altered risk of several types of cancers and pulmonary disease.…”

Association of microsomal epoxide hydrolase polymorphisms and lung cancer risk

“…The mEH polymorphisms in exons 3 and 4 were determined by two separate polymerase chain reaction (PCR)-based methods using primers as described by Harrison et al (1999). Briefly, the amplification reactions were carried out in a 50 ml volume consisting of 200 ng genomic DNA, 0.2 mM of each primer (VBCGenomics, Vienna, Austria), 0.2 mM deoxynuclotide triphosphate (Roche, Vienna, Austria), 1.5 mM MgCl 2 , 5 ml 10 Â PCR Buffer II (Applied Biosystems, Norwalk, CT, USA) and 1 U AmpliTaq DNA Polymerase (Applied Biosystems).…”

Low Microsomal Epoxide Hydrolase Expression is Associated with Bladder Carcinogenesis and Recurrence

“…Hence, mEH is a protective enzyme involved in general oxidative defenses against a number of environmental chemicals and pollutants (Harrison et al, 1999). However, mEH is also involved in the xenobiotic activation of tobacco carcinogens.…”