Xenobiotic-metabolizing enzymes and cancer risk: correspondence between genotype and phenotype

Metabolic activation and/or inactivation of a carcinogen is usually studied in appropriate in vitro systems but ultimately needs confirmation from in vivo studies, i.e. phenotype studies. It determines what initially happens to a carcinogen to which an organism is exposed. Consequently, it is of major importance to investigate the correspondence between any particular genotype of a carcinogen-metabolizing enzyme and its phenotypic expression, if any. The need to elucidate the relationship between genotype and phenotype is particularly important now, when methods for uncovering changes in genomic DNA are rather easy, even routine. There are several examples where the correspondence between a variant allele and an altered phenotype, measured by a probe drug or by some other means, has been elucidated (e.g. several alleles of CYP2D6). However, there are also cases where this correspondence has either not been studied (sometimes because of a lack of suitable probe substances) or has remained unclear (e.g. CYP1A1 or CYP2E1), despite case-control studies demonstrating an association between a variant allele and cancer risk. In the end one has to address the basic question as to how the genotype determines the phenotype and whether there is any biologically plausible link between the genotypic differences and cancer susceptibility. A knowledge of the complete sequence of events, from the gene to the outcome, would be helpful in unravelling the implications and possible preventive and treatment strategies to be employed in cases where clear associations between carcinogen-metabolizing enzymes and cancer susceptibility have been uncovered.