Metabolic competence and susceptibility of intestinal epithelium to genotoxic injury during regeneration.
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.
Patel
H R
HR
University Department of Surgery, the Medical School, University of Newcastle-upon-Tyne, UK.
Hewer
A
A
Phillips
D H
DH
Hayes
J D
JD
Wolf
C R
CR
Campbell
F C
FC
D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity; D018736:DNA Adducts / Q000032:analysis; D007414:Intestinal Neoplasms / Q000209:etiology; D007422:Intestines / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012038:Regeneration; D015262:Xenobiotics / Q000378:metabolism
D018736:DNA Adducts; D009153:Mutagens; D015262:Xenobiotics; D001564:Benzo(a)pyrene