Troglitazone selectively inhibits glyoxalase I gene expression.
OBJECTIVE
The hyperglycaemia associated with diabetes causes excessive production of cytotoxic methylglyoxal, an alpha-oxo-aldehyde. The glyoxalase system, composed of glyoxalase I and glyoxalase II, with glutathione (GSH) as the cofactor, plays an important role in the detoxification of alpha-oxo-aldehydes. We tested the hypothesis that troglitazone, an insulin-sensitizing drug previously used in the treatment of Type II (non-insulin-dependent) diabetes mellitus, up-regulates the glyoxalase system either by increasing phase 2 enzyme activities and thereby increasing cellular GSH, or, by inducing glyoxalase enzyme activities.


METHODS
Human astroglial cells, rat hepatocytes and cardiac myocytes were cultured and exposed to either troglitazone, or tertiary-butylhydroquinone (tBHQ, a phase 2 enzyme inducer). Glutathione content, advanced glycation end products (AGEs) and enzyme (glyoxalase I, glyoxalase II as well as the phase 2 enzymes, glutathione S-transferase and thioredoxin reductase) activities were determined. Glyoxalase I mRNA was also measured.


RESULTS
Troglitazone had no effect on cellular GSH nor phase 2 enzyme activities but significantly reduced the activities of glyoxalase I and II; this inhibitory effect was concentration-dependent and time-dependent and was associated with reduced mRNA contents and increased AGEs formation. Rosiglitazone had no effect on glyoxalase I gene expression. tBHQ, a classic phase 2 enzyme inducer, had no effect on the glyoxalase system but did increase glutathione contents and the activities of glutathione S-transferase and thioredoxin reductase.


CONCLUSIONS
Our study shows that troglitazone is a selective inhibitor of the glyoxalase system. This inhibition of the glyoxalase system could contribute to troglitazone's hepatotoxic action which has previously been reported in a small percentage of individuals.
Wu
L
L
Department of Anatomy and Cell Biology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
Eftekharpour
E
E
Davies
G F
GF
Roesler
W J
WJ
Juurlink
B H
BH
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001254:Astrocytoma; D018929:Cell Culture Techniques / Q000379:methods; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000201:enzymology*; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007700:Kinetics; D007791:Lactoylglutathione Lyase / Q000235:genetics*; D008099:Liver / Q000201:enzymology; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D013869:Thiolester Hydrolases / Q000235:genetics; D013997:Time Factors; D000077288:Troglitazone; D014407:Tumor Cells, Cultured; D000099301:Hydroxyacylglutathione Hydrolase
D000975:Antioxidants; D002839:Chromans; D005978:Glutathione; D006873:Hydroquinones; D007004:Hypoglycemic Agents; D007791:Lactoylglutathione Lyase; D013844:Thiazoles; D045162:Thiazolidinediones; D013869:Thiolester Hydrolases; D000077288:Troglitazone; D000099301:Hydroxyacylglutathione Hydrolase; C018855:2-tert-butylhydroquinone