Preferential increase of glutathione S-transferase class alpha transcripts in cultured human hepatocytes by phenobarbital, 3-methylcholanthrene, and dithiolethiones.
In rodents, a diversity of compounds are able to protect against acute and chronic toxicities of various xenobiotics including carcinogens, at least in part through induction of drug-metabolizing enzymes including glutathione S-transferase (GST) enzymes. We have posed the question as to whether or not these compounds also induce GSTs in human liver. Primary human hepatocyte cultures were exposed to phenobarbital, 3-methylcholanthrene, and two dithiolethiones [1,2-dithiole-3-thione and its 5-(2-pyrazinyl)-4-methyl derivative, oltipraz], and steady-state mRNA levels of GST classes alpha, mu, and pi were determined by Northern blot analysis. After 3 daily treatments, the two dithiolethiones were the most potent inducers; phenobarbital was also effective but to a lesser extent and 3-methylcholanthrene increased GST mRNA in only 2 of the 6 samples, although it stimulated cytochrome P-450 1A2 mRNA in all cell preparations. Whatever the compound only GSTA1 and/or A2 transcripts were induced. GST M1 mRNAs were not responsive or only slightly responsive, and GST P1 mRNAs, which were mostly undetectable in control cells, were not affected by treatment with any of the four chemicals. Large individual variations were observed in the level of induction of GST A1 and/or A2 mRNAs, and no sex difference could be demonstrated. These results clearly indicate that phenobarbital, 3-methylcholanthrene, and dithiolethiones are able to markedly increase mRNA levels of GST in human hepatocytes and that the GST alpha class is preferentially involved.
Morel
F
F
Inserm U49, Hôpital Pontchaillou, Rennes, France.
Fardel
O
O
Meyer
D J
DJ
Langouet
S
S
Gilmore
K S
KS
Meunier
B
B
Tu
C P
CP
Kensler
T W
TW
Ketterer
B
B
Guillouzo
A
A
D002478:Cells, Cultured; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008748:Methylcholanthrene / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D013871:Thiones / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
D011719:Pyrazines; D012333:RNA, Messenger; D013871:Thiones; D013876:Thiophenes; D008748:Methylcholanthrene; C026209:oltipraz; D005982:Glutathione Transferase; C049325:1,2-dithiol-3-thione; D010634:Phenobarbital