Oltipraz regulates different categories of genes relevant to chemoprevention in human hepatocytes.
Numerous chemical compounds are cytotoxic or carcinogenic to human beings and attention is now focusing on preventative strategies. One agent, oltipraz (OPZ), regarded as one of the most promising chemoprotectors, has been shown to be a potent inducer of phase II enzymes involved in the detoxification of carcinogens, including aflatoxins. However, little is known about its effects on global gene expression in human cells. Thus, we used microarrays and reverse transcription-quantitative polymerase chain reaction to test the effects of OPZ on the overall pattern of mRNA expression of multiple metabolic pathways in human hepatocytes in primary culture. Our results show for the first time that OPZ significantly alters the expression of human genes within different functional categories (detoxification of xenobiotics, antioxidant defences, xenobiotic transport, cell cycle and stress responses), at both the mRNA and protein levels, some of which are highly relevant to chemoprevention. Amongst these genes, several have never been described as being regulated by OPZ before. We also demonstrate variations in response to OPZ, depending on the individual from whom the cells were derived, that might potentially contribute to differences in efficacy of chemopreventive treatments between individuals. Moreover, comparison of our results with those obtained in rodents demonstrates species differences in response to OPZ for some genes, underlying the importance of studies on human cells to predict the effects of chemopreventive agents.
Piton
Amélie
A
INSERM U620, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, 35043 Rennes, France.
Le Ferrec
Eric
E
Langouët
Sophie
S
Rauch
Claudine
C
Petit
Elise
E
Le Goff
Frédérick
F
Guillouzo
André
A
Morel
Fabrice
F
D016588:Anticarcinogenic Agents / Q000494:pharmacology; D018890:Chemoprevention / Q000379:methods; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D011719:Pyrazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D013871:Thiones; D013876:Thiophenes
D016588:Anticarcinogenic Agents; D011719:Pyrazines; D012333:RNA, Messenger; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz