Metabolic Activation and Cytotoxicity of Fungicide Carbendazim Mediated by CYP1A2

Abstract

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.

In situ SERS imaging of protein-specific glycan oxidation on living cells to quantitatively visualize pathogen–cell interactions

“…It can be used for foliar spraying and soil treatment of plants, by changing the cell membrane and enzyme activity of pathogenic microorganisms, inhibiting their growth and reproduction, thereby protecting plants from disease damage and improving yield and quality. 36 CFP is a third-generation broad-spectrum semi synthetic cephalosporin, which can combat various types of degradation effect of lactamases with a wide antibacterial spectrum. 37 After FG (1 × 10 6 pcs per mL) was incubated with different doses of QCT (56 and 240 μg mL −1 ), CBZ (5 and 15 μg mL −1 ) and CFP (5 and 15 μg mL −1 ) for 6, 12 and 24 h, respectively, the drug treated FG was incubated with Au@Pt-DTNB/Apt treated MCF-7 cells for 120 min and then subjected to Raman imaging ( Fig.…”

CYP3A4-Mediated Metabolic Activation and Cytotoxicity of Chlortoluron

“…In addition, cells were treated with ketoconazole (KTC, a selective inhibitor of CYP3A, 10 μM) or vehicle for 1 h before the medium was discarded. Then, the cells were mixed with CTU at 25, 50, 100, and 200 μM, respectively, and cultured for another 12 h. 25 Separately, cells were mixed with 2,6-dichloro-4-nitrophenol (DCNP, a selective inhibitor of sulfotransferase, 10 μM) and incubated for 12 h at 37 °C. The resulting medium was discarded, and cells were mixed with CTU at 150 μM and cultured for 12 h. After that, the cells were collected and ultrasonicated.…”

Metabolic Activation and Cytotoxicity of Gramine Mediated by CYP3A in Rats

“…For example, fungicide carbendazim is catalyzed by CYP1A2 to generate reactive quinone imine intermediates that covalently bind to cellular proteins, resulting in cytotoxicity. 25 Similarly, diclofenac and omeprazole undergo similar metabolic activation process catalyzed by P450 enzymes, which is closely related to their cytotoxicity. 26,27 The present study aimed to explore the metabolic pathway of GRM in vitro and vivo, to identify the reactive metabolites of GRM, and to define the correlation between the metabolic activation and cytotoxicity of GRM.…”

“…Metabolic activation is commonly considered as one of the mechanisms of liver injury. For example, fungicide carbendazim is catalyzed by CYP1A2 to generate reactive quinone imine intermediates that covalently bind to cellular proteins, resulting in cytotoxicity . Similarly, diclofenac and omeprazole undergo similar metabolic activation process catalyzed by P450 enzymes, which is closely related to their cytotoxicity. , …”