Carbendazim
(CBZ) is a broad-spectrum fungicide widely used in
many nations for foliar spray as well as seed and soil treatment.
The resulting contamination and environmental pollution have been
drawing public attention. In particular, CBZ was reported to cause
liver damage in rats and zebrafish, and the mechanisms of its toxicity
have not been clarified. The purposes of this study were to investigate
the metabolic activation of CBZ and to determine a possible role of
the reactive metabolites in CBZ-induced liver injury reported. One
oxidative metabolite (M1), one glutathione conjugate (M2), and one N-acetyl cysteine conjugate (M3) were detected in human
and rat liver microsomal incubations fortified with glutathione or N-acetyl cysteine after exposure to CBZ. CYP1A2 was the
major enzyme responsible for the metabolic activation of CBZ. Biliary
M2 and urinary M3 were detected in rats treated with CBZ. CBZ-derived
protein adduction was found in cultured rat primary hepatocytes treated
with CBZ. The increase of administration concentration intensified
not only the cytotoxicity but also protein adduction induced by CBZ,
suggesting a correlation of the cytotoxicity with the observed protein
modification. The findings facilitate the understanding of the mechanisms
of toxic action of CBZ.