Expression of base excision repair enzymes in rat and mouse liver is induced by peroxisome proliferators and is dependent upon carcinogenic potency.
Elevated and sustained cell replication, together with a decrease in apoptosis, is considered to be the main mechanism of hepatic tumor promotion due to peroxisome proliferators. In contrast, the role of oxidative stress and DNA damage in the carcinogenic mechanism is less well understood. In view of possible induction of DNA damage by peroxisome proliferators, DNA repair mechanisms may be an important factor to consider in the mechanism of action of these compounds. Here, the ability of peroxisome proliferators to induce expression of base excision repair enzymes was examined. WY-14,643, a potent carcinogen, increased expression of several base excision DNA repair enzymes in a dose- and time-dependent manner. Importantly, expression of enzymes that do not repair oxidative DNA damage was not changed. Moreover, less potent members of the peroxisome proliferator group had much weaker or no effects on expression of DNA repair enzymes when compared with WY-14,643. Collectively, these data suggest that DNA base excision repair may be an important factor in peroxisome proliferator-induced carcinogenesis and that induction of DNA repair might provide further evidence supporting a role of oxidative DNA damage by peroxisome proliferators.
Rusyn
I
I
Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Denissenko
M F
MF
Wong
V A
VA
Butterworth
B E
BE
Cunningham
M L
ML
Upton
P B
PB
Thurman
R G
RG
Swenberg
J A
JA
D000818:Animals; D019757:Carbon-Oxygen Lyases / Q000235:genetics; D002273:Carcinogens / Q000633:toxicity*; D004249:DNA Damage; D045647:DNA Glycosylases; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D043223:Deoxyribonuclease IV (Phage T4-Induced); D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D008099:Liver / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009699:N-Glycosyl Hydrolases / Q000235:genetics; D018384:Oxidative Stress; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D020025:Peroxisome Proliferators; D011743:Pyrimidines; C006253:pirinixic acid; D004259:DNA-Directed DNA Polymerase; D043223:Deoxyribonuclease IV (Phage T4-Induced); D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; D019757:Carbon-Oxygen Lyases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase