Relevance of the Deletion Polymorphisms of the Glutathione S-Transferases GSTT1 and GSTM1 in Pharmacology and Toxicology

Abstract

Although cytosolic glutathione S-transferase (GST) enzymes occupy a key position in biological detoxification processes, two of the most relevant human isoenzymes, GSTT1-1 and GSTM1-1, are genetically deleted (non-functional alleles GSTT1*0 and GSTM1*0) in a high percentage of the human population, with major ethnic differences. The structures of the GSTT and GSTM gene areas explain the underlying genetic processes. GSTT1-1 is highly conserved during evolution and plays a major role in phase-II biotransformation of a number of drugs and industrial chemicals, e.g. cytostatic drugs, hydrocarbons and halogenated hydrocarbons. GSTM1-1 is particularly relevant in the deactivation of carcinogenic intermediates of polycyclic aromatic hydrocarbons. Several lines of evidence suggest that hGSTT1-1 and/or hGSTM1-1 play a role in the deactivation of reactive oxygen species that are likely to be involved in cellular processes of inflammation, ageing and degenerative diseases. There is cumulating evidence that combinations of the GSTM1*0 state with other genetic traits affecting the metabolism of carcinogens (CYP1A1, GSTP1) may predispose the aero-digestive tract and lung, especially in smokers, to a higher risk of cancer. The GSTM1*0 status appears also associated with a modest increase in the risk of bladder cancer, consistent with a GSTM1 interaction with carcinogenic tobacco smoke constituents. Both human GST deletions, although largely counterbalanced by overlapping substrate affinities within the GST superfamily, have consequences when the organism comes into contact with distinct man-made chemicals. This appears relevant in industrial toxicology and in drug metabolism.

Glutathione S-transferase M1 and T1 null genotypes increase susceptibility to drug-induced liver injury

“…From pharmacological studies, there are data showing that GST genotypes may be linked to DILI secondary to hepatocellular damage mechanisms based on the participation of GST enzymes in drug metabolism. 4 Thus, studying drugs in which the DILI mechanism is unknown or secondary to a hypersensitive reaction could be confusing. Most of these investigations have been performed in Asian patients exposed to antituberculosis drugs; it is known that GST enzymes play an important role in isoniazid metabolism.…”

“…The study of these genetic polymorphisms should be considered a target in the investigation of drugrelated hepatotoxicity mediated by metabolic idiosyncratic mechanisms. [2][3][4] However, in many cases, the drug-metabolism pathways and the exact mechanism and factors contributing to liver toxicity remain poorly understood. From pharmacological studies, there are data showing that GST genotypes may be linked to DILI secondary to hepatocellular damage mechanisms based on the participation of GST enzymes in drug metabolism.…”

Disinfection by-products exposure and intra-uterine growth restriction: Do genetic polymorphisms of CYP2E1or deletion of GSTM1 or GSTT1 modify the association?

“…Glutathione S-Transferase (GST) enzymes family play an important role in phase-2 biotransformation of xenobiotics and in cellular detoxification (Hayes and Strange 2000). However, mutations in genes modulating the activity of enzymes such as GSTT1 and GSTM1 may also be responsible for enhancing toxic activities of chemicals (Bolt and Thier 2006).…”

GST genotypes and lung cancer susceptibility in Asian populations with indoor air pollution exposures: A meta-analysis

“…The GSTM1 and GSTT1 enzymes have been shown to inhibit cellular damage from cytotoxic substances in in vitro studies [28]. The most common functional polymorphism in both the GSTM1 and GSTT1 genes is a deletion, which leads to a lack of function and decreased ability to detoxify electrophilic carcinogens efficiently [29]. Similarly, subjects carrying the GSTP1 Ile105Val Val/Val genotype have a lower ability to detoxify electrophilic compounds than subjects carrying the wildtype genotype, Ile/Ile [29].…”

“…The most common functional polymorphism in both the GSTM1 and GSTT1 genes is a deletion, which leads to a lack of function and decreased ability to detoxify electrophilic carcinogens efficiently [29]. Similarly, subjects carrying the GSTP1 Ile105Val Val/Val genotype have a lower ability to detoxify electrophilic compounds than subjects carrying the wildtype genotype, Ile/Ile [29]. Variants in these genes may reduce an individual's ability to detoxify PAHs and could increase risk for various cancers, including lung cancer [30;31].…”