Isoniazid-induced hepatotoxicity and neurotoxicity in rats investigated by 1H NMR based metabolomics approach

Abstract

Isoniazid (INH) is a well-known therapeutic and preventive agent against tuberculosis. However, high rates of side effects with various symptoms concerning hepatotoxicity and neurotoxicity have been reported, hindering its wide and safe application in clinic. In this investigation, rats were intoxicated with INH by gavage at doses of 200 and 400 mg/kg for 7 consecutive days to develop a rat model of acute INH-induced toxicity, which was investigated by a ¹H NMR-based metabolomics complemented with clinical assays, histopathological inspection and western blotting. INH decreased the weights of dosed rats and induced seizure and hepatic steatosis dose-dependently. Orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS-DA) of the NMR profiles of rat livers, brains and serum revealed that INH dose-dependently induced oxidative stress, disorders of excitatory and inhibitory amino acid neurotransmitters, and disturbances of energy metabolism and osmotic balance, which could help clarify the mechanisms of INH-induced hepatotoxicity and neurotoxicity. This integrated metabolomics approach showcased its ability to characterize the global metabolic status of organism, providing a powerful and feasible tool to probe drug induced toxicity or side effects.

Keywords: Correlation network analysis; Hepatotoxicity; Isoniazid; Metabolomics; NMR; Neurotoxicity.