Investigations on the effects of oltipraz on the nucleotide excision repair in the liver.
Recent studies support the view that in addition to its effect on both phase I and phase II xenobiotic metabolizing enzymes, the synthetic chemopreventive agent oltipraz also increases the nucleotide excision repair (NER) which represents the major pathway of elimination of chemical carcinogen DNA adducts. Since most carcinogens are activated in the liver, we investigated the influence of oltipraz on NER activity of this target tissue by using two different approaches. First, we employed an assay based on the measurement of DNA repair in cisplatin-damaged plasmid DNA incubated in the presence of cell-free extracts prepared from either rat liver or human hepatoma HepG2 cells treated by oltipraz. Secondly, we analyzed the removal of aflatoxin B(1)-derived DNA adducts formed in primary human hepatocytes exposed to oltipraz after treatment with this mycotoxin. Whatever the strategy used, NER activity was not altered in liver cells. These data demonstrated that liver cells actively repair bulky DNA adducts by NER and that oltipraz does not influence their NER activity neither in vivo nor in vitro, consequently strongly suggesting that the chemopreventive agent oltipraz is acting before the initiation step of cancer development.
Sparfel
Lydie
L
INSERM U456, Détoxication et Réparation Tissulaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, 2 avenue Léon Bernard, 35043 cédex, Rennes, France.
Langouët
Sophie
S
Fautrel
Alain
A
Salles
Bernard
B
Guillouzo
André
A
D016604:Aflatoxin B1 / Q000494:pharmacology; D000818:Animals; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D018736:DNA Adducts / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects* / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000502:physiology; D008297:Male; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D013871:Thiones; D013876:Thiophenes
D018736:DNA Adducts; D011719:Pyrazines; D018894:Reverse Transcriptase Inhibitors; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D004247:DNA; D016604:Aflatoxin B1