Carcinogenesis, Vol 18, 2171-2177, Copyright © 1997 by Oxford University Press
HR Patel, A Hewer, DH Phillips, JD Hayes, CR Wolf and FC Campbell
The carcinogenic potency of many mutagens is increased in conditions of
tissue regeneration. This involves fundamental changes of cellular division
and differentiation, in intestinal epithelium. However, effects on
epithelial capacity for carcinogen metabolism and susceptibility to
genotoxic injury are unknown. Using a novel rat model, this study assessed
expression of cytochrome P450 mono- oxygenases (Cyps), glutathione
S-transferases (GSTs) and uridine diphosphoglucuronosyl transferase (UGT)
in intestinal epithelium during sequential stages of regeneration. Enzyme
induction and DNA adduct formation were also assessed after benzo[a]pyrene
(BaP) exposure. Control assays were carried out in normal intestinal
epithelium. Fewer phase I and II xenobiotic metabolizing enzymes were
expressed in regenerating intestinal epithelium than in 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 epithelium but induction increased
by >2- fold at late stage regeneration. Higher levels of benzo[a]pyrene
7,8- diol-9,10-epoxide (BPDE) DNA adducts were formed at early stages of
regeneration, than at later stages. Intestinal epithelium displayed reduced
metabolic competence and differential susceptibility to genotoxic injury
from BaP, during regeneration.
ARTICLES
Metabolic competence and susceptibility of intestinal epithelium to genotoxic injury during regeneration
University Department of Surgery, the Medical School, University of Newcastle-upon-Tyne, UK.
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