Association of the CYP1A1*2A, GSTT1 null, GSTM1 null, mEPHX*3, and XRCC1-399 genetic polymorphisms with ulcerative colitis

Abstract

Dear Editor: Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) that affects the large intestine and rectum. IBDs are believed to result from the interplay between a number of disease genes and environmental factors. Epidemiological data provide evidence that genetic predisposition to ulcerative colitis depends on the contribution of multiple genes rather than a single genetic factor. Recently, the number of ulcerative colitis-associated loci and genes, such as ECM1, IL23R, IL12B, HLA, NKX2-3, and VDR, has increased. However, mutations within these genes were absent in the majority of patients, suggesting the presence of additional susceptibility genes. It is suggested that reactive molecules, such as reactive oxygen species ROS, may play a pivotal role in the mechanism of inflammation by altering the intestinal permeability, which leads to tissue injury in the mucosa, ultimately resulting in tissue damage. Reactive molecules may be products of the endogenous metabolism of xenobiotics catalyzed by biotransformation enzymes. Changes in detoxification of xenobiotics that cause epithelial damage may confer susceptibility to UC. Chronic inflammation of the colon may further lead to carcinogenesis and tumor formation. Hence, polymorphic enzymes involved in the detoxification processes may be risk factors of UC and colon cancer. Biotransformation enzymes such as cytochrome P450s and GSTs perform vital roles in the metabolism of xenobiotics and ROS. They often convert parent compounds into highly reactive metabolites, such as epoxides, that may bind to cellular components and induce tissue damage and carcinogenesis. Detoxification of these reactive metabolites is carried out by either conjugating with glutathione, which is catalyzed by GSTs, or by hydration, which is catalyzed by epoxide hydrolases. X-ray repair cross-complementing groups (XRCCs) are important proteins of the DNA repair pathways. The XRCC1 gene is responsible for a scaffolding protein that directly associates with the processes of base excision repair or single-strand break repair. Numerous polymorphisms that result in altered enzyme activities have been described in the genes of these enzymes. It has been suggested that individual variations in the susceptibility to the mutagenic and carcinogenic activity of xenobiotics may be partially explained by differences in their activation and deactivation pathways. As chemical and oxidative stress may be involved in the etiology of ulcerative colitis, polymorphic genes encoding for these biotransformation enzymes may modulate the genetic susceptibility to ulcerative colitis and carcinogenesis in the colon. Therefore, this study was undertaken to determine whether genetic polymorphisms in biotransformation enzymes in patients with ulcerative colitis differ from those in healthy controls. Polymorphisms in genes encoding cytochrome P450 1A1 (CYP1A1), glutathione S-transferase mu-1 (GSTM1) and theta-1 (GSTT1), microsomal epoxide hydrolase (EPXH) and X-ray repair complementing group 1 (XRCC1) were investigated. The present case–control study was performed in subjects recruited between 2008 and 2010. A total of 161 consecutive patients with ulcerative colitis (94 males, 67 females; all Caucasian) consulting the outpatient clinic of the Department O. Buyukgoze : S. Arslan :A. Sen (*) Biology Department, Faculty of Arts & Sciences, Pamukkale University, Kinikli Campus, Kinikli, 20070, Denizli, Turkey e-mail: sena@pau.edu.tr