Effects of chlorpyrifos on non-cholinergic toxicity endpoints in immortalized and primary rat hepatocytes under normal and hepatosteatotic conditions.

Chlorpyrifos (CPS) is the most widely used organophosphate (OP) insecticide. Non-cholinergic targets of OPs include enzymes belonging to the serine hydrolase family. Carboxylesterases (Ces) are involved in detoxication of xenobiotics as well as lipid metabolism in the liver. Monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) are responsible for hydrolyzing endocannabinoids and can also be inhibited by OP compounds. However, there are no in vitro studies examining the sensitivities of these non-cholinergic endpoints following CPS exposure in the steatotic liver. Therefore, we determined the effects of CPS on these endpoints in immortalized McArdle-RH7777 (MCA) hepatoma cells and primary rat hepatocytes under normal and steatotic conditions. Ces activity was more sensitive to inhibition than MAGL or FAAH activity following exposure to the lowest CPS concentration. Additionally, Ces and MAGL activities in steatotic primary hepatocytes were less sensitive to CPS mediated inhibition than those in normal primary hepatocytes, whereas Ces inhibition was more pronounced in steatotic MCA cells. These findings suggest that steatotic conditions enhance the inhibition of hepatic serine hydrolases following exposure to CPS in an enzyme- and cell type-specific manner. CPS-mediated inhibition of these enzymes may play a part in the alterations of hepatic lipid metabolism following OP exposures.