Decreased Detoxification of the Reactive or Toxic Metabolite

Bioinactivation of toxic metabolites can be nonenzymatic, for example, conjugation with glutathione. However, in many cases, detoxification may be catalyzed by a number of enzymes. In this respect, the glutathione-S-transferases (GST) have attracted a great deal of interest, in particular in the field of cancer, where deficient detoxification of environmentally derived carcinogens, for example, from smoking, has been implicated in the pathogenesis of cancer (82,83). However, the GST superfamily, many members of which are polymorphically expressed (84), is also important in the detoxification of drugs, and thereby in the pathogenesis of ADRs. There are three examples where GST polymorphisms have been shown to play a possible role:

1. Cisplatin is an agent widely used in the treatment of epithelial malignancies. Cisplatin ototoxicity is an important ADR that may be due to oxidative stress. In a study of 20 patients with cisplatin ototoxicity, analysis of polymorphisms in five GST genes, showed that the carriage of the GSTM3*B allele may be protective (85).

2. Tacrine, an anticholinesterase used in Alzheimer's disease, caused transaminitis in up to 50% of the patients. Analysis of the GSTM1 and GSTT1 polymorphisms in a French cohort showed that individuals who had deficiencies of both GSTM1 and GSTT1 were more susceptible to tacrine hepatotoxicity (86). However, this was not replicated in a North American cohort (87,88).

3. Troglitazone was the first of a new class of antidiabetic agents, which was withdrawn from the market because of its potential to cause severe, and sometimes, fatal hepatotoxicity. In a study of 110 Japanese patients who had been prescribed troglitazone, an evaluation of 68 polymorphic sites in 51 candidate genes involved in drug metabolism, apoptosis, production, and elimination of reactive oxygen species, PPARy2 and insulin, showed that a strong correlation with transaminase elevations was observed only in patients with the combined glutathione-S-transferase GSTT1-GSTM1 null genotype (89).

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