Protein Adduction and Hepatotoxicity Induced by Stiripentol

Stiripentol (STP) is a kind of effective antiepileptic medicine, but its hepatotoxicity has been documented. However, the cause of its hepatotoxicity remains unclear. In this study, we attempted to explain its hepatotoxicity from the perspective of protein adduction derived from STP. We proposed that STP could produce an electrophilic carbonium ion, which formed hepatic GSH conjugation and protein adduction, and the carbonium ion was produced through two pathways, spontaneous dehydration and sulfation catalyzed by sulfotransferases (SULTs). STP-derived glutathione (GSH) conjugate was found in chemical reaction systems involving STP and GSH, which indicates that STP can undergo spontaneous dehydration to produce a carbonium ion. Increased GSH conjugate was observed in mouse liver cytosol incubation supplemented with GSH in the presence of the sulfation cofactor 3'-phosphoadenosyl-5'-phosphosulfate, which indicates that sulfation metabolism by SULTs can accelerate the production of carbonium ions. GSH conjugation and protein adduction were found in the livers of STP-treated mice and mouse primary hepatocytes, and 2,6-dichloro-4-nitrophenol, an inhibitor of SULTs, displayed an inhibitory effect on them. Serum alanine aminotransferase and aspartate aminotransferase activities in STP-treated mice and cytotoxicity in mouse primary hepatocytes displayed dose- and concentration-dependent trends, respectively, as did protein adduction. L-Buthionine-sulfoximine co-treatment potentiated the protein adduction and the susceptibility of hepatocytes to the cytotoxicity of STP. These findings suggest that protein adduction is responsible for STP-induced hepatotoxicity, and GSH serves a detoxification function against protein adduction.