Benzbromarone aggravates hepatic steatosis in obese individuals

As a widely used anti-gout drug, benzbromarone has been found to induce hepatic toxicity in patients during clinical treatment. Previous studies have reported that benzbromarone is metabolized via cytochrome P450, thus causing mitochondrial toxicity in hepatocytes. In this study, we found that benzbromarone significantly aggravated hepatic steatosis in both obese db/db mice and high fat diet (HFD)-induced obese (DIO) mouse models. However, benzbromarone had less effect on the liver of lean mice. It was found that the expression of mRNAs encoding lipid metabolism and some liver-specific genes were obviously disturbed in benzbromarone-treated DIO mice compared to the control group. The inflammatory and oxidative stress factors were also activated in the liver of benzbromarone-treated DIO mice. In accordance with the in vivo results, an in vitro experiment using human hepatoma HepG2 cells also confirmed that benzbromarone promoted intracellular lipid accumulation under high free fatty acids (FFAs) conditions by regulating the expression of lipid metabolism genes. Importantly, prolonged treatment of benzbromarone significantly increased cell apoptosis in HepG2 cells in the presence of high FFAs. In addition, in benzbromarone-treated hyperuricemic patients, serum transaminase levels were positively correlated with patients' obesity level.

This study demonstrated that benzbromarone aggravated hepatic steatosis in obese individuals, which could subsequently contribute to hepatic cell injury, suggesting a novel toxicological mechanism in benzbromarone-induced hepatotoxicity.