Abstract.
Aims/hypothesis:
The hyperglycaemia associated with diabetes causes excessive production of cytotoxic methylglyoxal, an α-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 α-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.
Conclusion/interpretation:
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. [Diabetologia (2001) 44: 2004–2012]
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Received: 26 February 2001 and in revised form: 12 July 2001
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Wu, L., Eftekharpour, E., Davies, G. et al. Troglitazone selectively inhibits glyoxalase I gene expression. Diabetologia 44, 2004–2012 (2001). https://doi.org/10.1007/s001250100004
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DOI: https://doi.org/10.1007/s001250100004