Polymorphism at CYP and GST gene loci and susceptibility to tobacco related cancers

Abstract

Exposure to synthetic or natural chemical compounds present in the environment is causally associated with a large proportion of human cancers. Xenobiotic metabolizing enzymes (XMEs) are responsible for the metabolism of many of these exogenous chemicals that are toxic, mutagenic and/ or carcinogenic. The XMEs comprise of phase I enzymes that ate involved in the bioactivation of several carcinogens, and phase II enzymes that take part in detoxification by conjugatiion the electrophilic compounds formed by the phaxe I enzymes with small bio-molecules (e.g. glutathione). Hence, the toxicological outcome of exposure, absorption and activation/detoxfication of xenobiotes depends on a delicate balance between the phase I and II enzymes. Polymorphism at genes encoding these enzymes can thus result in altered metabolism and result in toxicity or mutagenicity thereby altering individual susceptibility to diseases caused by environmental agents. Many studies have been conducted on the potential association between polymorphic expression of CYP1A1, CYP2D6, GSTM1, GSTM3, GSTP1, GSTT1 and various types of environmentally induced cancers, particularly those that are related to tobaccl abuse. CYP1A1, CYP2D6 and CYP2E1 polymorphic alleles have been associated with susceptibility to lung, and head and neck cancers. Apart from modulating head and aneck cancer risk, polymouphisms at GSTM1, GSTM3,GSTP1 and GSTT1 gene loci have also been involved in a variety of tobaccl associated cancers like lung, bladder and oesophageal cancer. The relationship between polymorphisms at metabolic gene loci and cancer risk is known to vary in distinct ethnic groups. This suggests that the variant alleles can not serve as universal biomarkers o susceptibility to environmental carcinogens. Studies on polymorphism at CYP and GST gene loci that have identified host factors responsible for modifying susceptibility to tobaccl-related cancers are documented in this review.