GENETICS OF GLUTATHIONE S-TRANSFERASES AND COMPLEX DISEASES

Abstract

The glutathione-S-transferases (GSTs) are dimeric cytosolic xenobiotic-metabolizing enzymes that catalyze the conjugation of an active xenobiotic to GSH, an endogenous water-soluble substrate. The GST-mediated detoxification pathway ensures cellular protection from environmental insults and oxidative stress. Cellular ROS/RNS levels promote peroxidation of lipids and lipoproteins present in biomembranes, which leads to development of several pathological conditions. GSTs protect cells against deleterious actions of ROS/ RNS by promoting redox homeostasis through neutralization of excessive reactive metabolites, whose chemical actions elicit numerous signaling cascades associated with cell proliferation, inflammatory responses, apoptosis and senescence. Human GSTs are divided into three main families, namely, cytosolic (α-, β-, γ-, δ-, ξ-and ζ), mitochondrial (π) and membrane-bound (k).These classes of GSTs originate from different chromosomes but share ~30% sequence identity and have cell specific distribution. Genetic variants in antioxidant enzyme encoding genes lead to decreased enzymatic activity leading to oxidative DNA damage and chronic inflammation. Moreover, genetic variants in GSTM1, T1 and P1 have been reported to be involved in development of type 2 diabetes mellitus (T2DM) and various cancers like cervical (CaCx), bladder, colon, gastrointestinal, lung, pulmonary diseases, neurological disorders and various pathological phenotypes. Interestingly, some of the common genetic variants like GSTM1-Del (16kb deletion), GSTT1-Del (54kbdeletion) polymorphisms (Null/Present) and GSTP1 +313A/G (105I/V rs1695) are significantly associated with complex diseases viz. T2DM and CaCx in north Indian population as well as other ethnic groups. The GST genetic variants have also shown interesting association with treatment outcome in cervical cancer patients undergoing chemoradiotherapy viz. clinical response, vital status, overall survival and toxicity. In addition to the above, this chapter focuses on the importance of functional aspect of polymorphic variants in different populations so that the risk genotypes can be identified as indicators of disease susceptibility. Genetic studies will help to develop prognostic biomarkers for early prediction and risk assessment in patients and enable clinicians to develop personalized treatment regimes. © 2020 by Nova Science Publishers, Inc. All rights reserved.