Omeprazole (OPZ) is a proton pump inhibitor commonly
used for the
treatment of gastric acid hypersecretion. Studies have revealed that
use of OPZ can induce hepatotoxicity, but the mechanisms by which
it induces liver injury are unclear. This study aimed to identify
reactive metabolites of OPZ, determine the pathways of the metabolic
activation, and define the correlation of the bioactivation with OPZ
cytotoxicity. Quinone imine-derived glutathione (GSH), N-acetylcysteine (NAC), and cysteine (Cys) conjugates were detected
in OPZ-fortified rat and human liver microsomal incubations captured
with GSH, NAC, or Cys. The same GSH conjugates were detected in bile
of rats and cultured liver primary cells after exposure to OPZ. Similarly,
the same NAC conjugates were detected in urine of OPZ-treated rats.
The resulting quinone imine was found to react with Cys residues of
hepatic protein. CYP3A4 dominated the metabolic activation of OPZ.
Exposure to OPZ resulted in decreased cell survival in cultured primary
hepatocytes. Pretreatment with ketoconazole attenuated the susceptibility
of hepatocytes to the cytotoxicity of OPZ.
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.
Deferasirox (DFS) is used for the treatment of iron accumulation caused by the need for long-term blood transfusions, such as thalassemia or other rare anemia. Liver injury due to exposure to DFS has been documented, and the toxic mechanisms of DFS are unknown. The present study aimed to investigate the reactive metabolites of DFS in vitro and in vivo to help us understand the mechanisms of DFS hepatotoxicity. Two hydroxylated metabolites (5-OH and 5'-OH) were identified during incubation of DFS-supplemented rat liver microsomes. Such microsomal incubations fortified with glutathione (GSH) or N-acetylcysteine (NAC) as capture agents offered two GSH conjugates and two NAC conjugates. These GSH conjugates and NAC conjugates were also detected in bile and urine of rats given DFS. CYP1A2 and CYP3A4 were found to dominate the metabolic activation of DFS. Administration of DFS induced decreased cell survival in cultured primary hepatocytes. Pretreatment with ketoconazole and 1-aminobenzotrizole made hepatocytes less susceptible to the cytotoxicity of DFS.
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