We reported previously that glucagon decreased alpha- and pi-class glutathione S-transferases (GSTs) and microsomal epoxide hydrolase (mEH) protein levels in primary cultured rat hepatocytes. The present study examines the effects of protein kinase A (PKA) inhibitor, KT5720, on the glucagon-mediated decrease in expression of GSTs and mEH. To assess cell viability, lactate dehydrogenase release and MTT activity were examined in hepatocytes treated KT5720. Cell viability was significantly decreased in a concentrationdependent manner after incubation with KT5720 at the concentrations of 1 ?M or above for 24 h, which was inhibited by the cytochrome P450 inhibitor SKF-525A. In contrast, another PKA inhibitor H89 (up to 25 ?M) was not toxic to hepatocytes. The glucagon-mediated decrease in expression of alpha- and pi-class GSTs and mEH was completely inhibited by 25 ?M H89 and attenuated by 0.1 ?M KT5720. This study demonstrates that KT5720 may cause cytotoxicity in rat hepatocytes through cytochrome P450-dependent bioactivation. The present study implicates PKA in mediating the inhibitory effect of glucagon on expression of alpha- and piclass GSTs and mEH.
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