Effects of microsomal enzyme inducers on glutathione S-transferase isoenzymes in livers of rats and hamsters.
The effects of microsomal enzyme inducers on glutathione S-transferase (GST) isoenzymes were studied in livers of rats and hamsters using three hypolipidemic drugs of the peroxisome proliferator type and the two model substances phenobarbital (PB) and 3-methylcholanthrene (MC). The effects were investigated by immunoblot analysis of the various GST subunits using polyclonal antibodies directed to rat subunits 1-4. In untreated animals the subunit composition was different, with hamsters having a much higher content of class mu isoenzymes. Administration of all three hypolipidemic drugs reduced the protein concentration of both alpha and mu class GSTs in rats but reduced only class mu subunits in hamsters. This reduction was in good agreement with the decreased activity observed with the broad-spectrum substrate 1-chloro-2,4-dinitrobenzene (CDNB) in both species. As expected, PB and MC increased GST activity together with the concentration of subunits 1 and 3 in rats. In hamsters, PB significantly increased subunit 1 and slightly reduced subunits 3 and 4, although this decrease was not significant. Total GST, measured with CDNB, was reduced by 17%. In contrast, MC slightly decreased subunit 1 and markedly raised subunits 3 and 4, resulting in a net increase in total GST activity. All drugs increased relative liver weight, microsomal protein concentration and total P450 in both species; in contrast, total cytosolic proteins were raised by all drugs in rats but not in hamsters, except for MC. The results obtained in these two species show that GST activity is not always increased by microsomal enzyme inducers. The response may depend in part on isoenzyme profile, and varies with the subunit considered.
Foliot
A
A
INSERM U 75, Université René Descartes, CHU Necker, Paris, France.
Beaune
P
P
D000818:Animals; D002994:Clofibrate / Q000494:pharmacology; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D003600:Cytosol / Q000201:enzymology; D004790:Enzyme Induction / Q000187:drug effects; D011345:Fenofibrate / Q000494:pharmacology; D005982:Glutathione Transferase / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D009255:Nafenopin / Q000494:pharmacology; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity
D007527:Isoenzymes; D009255:Nafenopin; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase; D002994:Clofibrate; D011345:Fenofibrate