Genetic variability in susceptibility and response to toxicants

Everyone has a unique combination of polymorphic traits that modify suscept ibility and response to drugs, chemicals and carcinogenic exposures. The me tabolism of exogenous and endogenous chemical toxins may be modified by inh erited and induced variation in CYP (P450), acetyltransferase (NAT) and glu tathione S-transferase (GST) genes. We observe that specific 'at risk' geno types for GSTM1 and NAT1/2 increase risk for bladder cancer among smokers. Genotypic and phenotypic variation in DNA repair may affect risk of somatic mutation and cancer. Variants of base excision and nucleotide excision rep air genes (XRCC1 and XPD) appear to modify exposure-induced damage from cig arette smoke and radiation. We are currently engaged in discovering genetic variation in environmental response genes and determining if this variatio n has any effect on gene function or if it is associated with disease risk. These and other results are discussed in the context of evaluating inherit ed or acquired susceptibility risk factors for environmentally caused disea se. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.