Metabolism of Chemotherapeutic Agents

tenable, although the failure to define precise roles for individual GST has hampered assessment of the implications of polymorphism as selection of diseases whose pathogenesis may be affected is subjective. Thus while associations between GST genotypes and clinical pheno-type have been reported they cannot be predicted, and it is unclear why some, but not other, links are significant. Further, study reproducibility is a problem, probably because of variable definition of phenotypes and differences in population characteristics. Thus molecular epidemiological studies show that the impact of polymorphism on disease risk and outcome is likely to be most evident in patient subgroups.[1] Such subgroups may be defined by different sets of susceptibility genes and/or environmental exposures and identified by clinical characteristics such as tumor site, age at diagnosis, or gender. For example, the importance of exposure is shown by the chemoprotective effect of cruciferous vegetable-derived metabolites such as isothiocyanates that modulate cytochrome P450 and GST expression.1-1,2-1 Thus GST polymorphisms may influence cancer risk through various mechanisms including interactions with diet-derived compounds. The GST effect may also be exerted via their catalysis of detoxication reactions or by interactions with peptides that mediate signaling pathways.

While most significant associations between GST genotypes and clinical phenotype have not been replicated, a minority have been independently confirmed. For example, GSTP1 Val105/Val105 has been associated with reduced risk of airway hyperresponsiveness (odds ra-tio=0.23-0.38) in three studies in asthmatic adults and children.[20] This genotype is also protective against childhood respiratory illness.[21] The advent of high-throughput genotyping, availability of new SNP, and ease of deriving haplotypes should place an emphasis on large studies incorporating some assessment of reproducibility. Furthermore, assessment of further allelic GST sites associated with binding of peptides involved with cell signaling warrants further investigation.

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