Genetic variability in susceptibility and response to toxicants

Xenobiotic metabolism is carried out by phase I and phase II enzymes which are to a large extent polymorphic. The majority of cytochrome P450 (CYP) enzymes involved in xenobiotic metabolism are polymorphic and inducible, resulting in abolished, quantitatively or qualitatively altered or enhanced drug metabolising activity. Stable duplication, multiduplication or amplification of active genes have been described. In mouse models it is apparent that inactivation of specific enzymes active in xenobiotic metabolism can affect the risk for cancer development in relation to specific xenobiotic exposure, whereas the situation in humans is far more complex. The polymorphism of CYP enzymes is expected to influence individual sensitivity and toxicity for different environmental agents, although there is as yet no real consensus in the literature about specific firm relationships in this regard. The incidence of serious and fatal adverse drug reactions (ADRs) has been found to be very high among hospitalised patients, the cost of ADRs to society is large and they are responsible for 5-10% of all hospital admissions. It is likely that predictive genotyping could avoid 10-20% of ADRs. In the present contribution an overview is presented regarding our present knowledge about the polymorphism of phase I enzymes, with emphasis on xenobiotic metabolising CYPs and the importance for metabolic activation of xenobiotics.