METABOLIC COMPETENCE AND SUSCEPTIBILITY OF INTESTINAL EPITHELIUM TO GENOTOXIC INJURY DURING REGENERATION

The carcinogenic potency of many mutagens is increased in conditions o f tissue regeneration, This involves fundamental changes of cellular d ivision and differentiation, in intestinal epithelium. However, effect s on epithelial capacity for carcinogen metabolism and susceptibility to genotoxic injury are unknown, Using a novel rat model, this study a ssessed expression of cytochrome P450 mono-oxygenases (Cyps), glutathi one S-transferases (GSTs) and uridine diphosphoglucuronosyl transferas e (UGT) in intestinal epithelium during sequential stages of regenerat ion, Enzyme induction and DNA adduct formation were also assessed afte r benzo[a]pyrene (BaP) exposure, Control assays were carried out in no rmal intestinal epithelium. Fewer phase I and II xenobiotic metabolizi ng enzymes were expressed in regenerating intestinal epithelium than i n normal control intestinal epithelium (GSTA3, UGT in regeneration vs Cyp2B, GSTA1/2, GSTA4, GSTP1, UGT in control), Benzo[a]pyrene induced GSTA3 and UGT in regeneration vs Cyp1A, Cyp2B, GSTA1/2, GSTA3, GSTA4, GSTP1 and UGT in control normal intestinal epithelium. Benzo[a]pyrene induced low levels of GSTA3 in early regenerating intestinal epitheliu m but induction increased by >2-fold at late stage regeneration, Highe r levels of benzo[a]pyrene 7,8-diol-9,10-epoxide (BPDE) DNA adducts we re formed at early stages of regeneration, than at later stages,]intes tinal epithelium displayed reduced metabolic competence and differenti al susceptibility to genotoxic injury from BaP, during regeneration.