Troglitazone (TGZ) was developed for the treatment of type 2 diabetes but was 
withdrawn from the market due to hepatotoxicity. The formation of reactive 
metabolites has been associated with the observed hepatotoxicity. Such reactive 
metabolites have been proposed to be formed via three different mechanisms. One 
of the proposed mechanisms involves the oxidation of the chromane moiety of TGZ 
to a reactive o-quinone methide. The two other mechanisms involve metabolic 
activation of the thiazolidinedione moiety of TGZ. In the present study, it is 
shown that electrochemical oxidations can be used to generate a reactive 
metabolite of TGZ, which can be trapped by GSH or N-acetylcysteine. From 
incubations of TGZ with rat and human liver microsomes in the presence of either 
GSH or N-acetylcysteine, it was shown that similar conjugates were formed in 
vitro as formed from electrochemical oxidations of TGZ. One- and two-dimensional 
NMR studies of the troglitazone- S-( N-acetyl)cysteine conjugate revealed that 
N-acetylcysteine was attached to a benzylic carbon in the chromane moiety, 
showing that the conjugate was formed via a reaction between the o-quinone 
methide of TGZ and N-acetylcysteine. From electrochemical oxidations of 
rosiglitazone, pioglitazone, and ciglitazone in the presence of GSH, no GSH 
conjugates could be identified. These three compounds all contain a 
thiazolidinedione moiety. In conclusion, it has been shown that the primary 
reactive metabolite of TGZ formed from electrochemical oxidation was the 
o-quinone methide, and this metabolite was similar to what was observed to be 
the primary reaction product in human and rat liver microsomes.