Metformin administration induces hepatotoxic effects in paraoxonase-1-deficient mice

•Studies have reported toxic effects of metformin in patients with liver disease.•PON1 is an antioxidant enzyme synthesized mainly by the liver.•We found that metformin administration increases steatosis and inflammation in PON1-deficient mice.•PON1 deficiency is associated with toxic effects of metformin in the liver.

Metformin is the first-line pharmacological treatment of diabetes. In these patients, metformin reduces body weight and decreases the risk of diabetes-related complications such as cardiovascular disease. However, whether metformin elicits beneficial effects on liver histology is a controversial issue and, as yet, there is no consensus. Paraoxonase-1 (PON1), an enzyme synthesized mainly by the liver, degrades lipid peroxides and reduces oxidative stress. PON1 activities are decreased in chronic liver diseases. We evaluated the effects of metformin in the liver of PON1-deficient mice which, untreated, present a mild degree of liver steatosis. Metformin administration aggravated inflammation in animals given a standard mouse chow and in those fed a high-fat diet. Also, it was associated with a higher degree of steatosis in animals fed a standard chow diet. This report is a cautionary note regarding the prescription of metformin for the treatment of diabetes in patients with concomitant liver impairment.