Metabolic Activation of Gemfibrozil Mediated by Cytochrome P450 Enzymes and Sulfotransferases.

Gemfibrozil (GEM), a lipid regulator, is a fibric acid derivative widely used in the treatment of hyperlipidemia. It has been reported that GEM can induce acute liver injury in the course of therapy in clinical practice, so it is necessary to elucidate the mechanisms of toxic action. The present study focused on metabolic activation of GEM, possibly participating in GEM-mediated liver injury. A benzylic alcohol metabolite (M1), along with a phenol metabolite (M2), was detected in microsomal incubations, rat primary hepatocyte culturing, and rats given GEM. A GSH conjugate (M3) was detected in cultured rat hepatocytes after exposure to GEM. Formation of M1 was found to be NADPH dependent, and generation of M3 required M1 and 3'-phosphoadenosine-5'-phosphosulfate. It is most likely that GEM was biotransformed to M1, which was further metabolized to a sulfate. The resulting sulfate was reactive to bio-thiols. Cytochrome P450 and sulfotransferases participated in the phase I and phase II reactions, respectively. M1 and M3 were chemically synthesized, and their structures were characterized by mass spectrometry and NMR. The present study has particular value for elucidating the mechanism of liver injury caused by GEM.