Involvement of Reactive Metabolites of Diclofenac in Cytotoxicity in Sandwich-Cultured Rat Hepatocytes

Background and Objectives: Diclofenac (DIC) is metabolized to reactive metabolites such as diclofenac acyl-β-d-glucuronide (DIC-AG). It is possible that such reactive metabolites could cause tissue damage by formation of covalent protein adducts and other modification of cellular proteins or by indu...

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Published in:International journal of toxicology 2017-05, Vol.36 (3), p.260-267
Main Authors: Kawase, Atsushi, Hashimoto, Ryota, Shibata, Mai, Shimada, Hiroaki, Iwaki, Masahiro
Format: Article
Language:English
Subjects:
Animals
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Anti-Inflammatory Agents, Non-Steroidal - toxicity
Cell Survival - drug effects
Cells, Cultured
Chemical and Drug Induced Liver Injury - metabolism
Diclofenac - analogs & derivatives
Diclofenac - metabolism
Diclofenac - pharmacology
Diclofenac - toxicity
Glucuronides - metabolism
Hepatocytes - drug effects
Hepatocytes - metabolism
Male
Rats, Sprague-Dawley
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Summary:Background and Objectives: Diclofenac (DIC) is metabolized to reactive metabolites such as diclofenac acyl-β-d-glucuronide (DIC-AG). It is possible that such reactive metabolites could cause tissue damage by formation of covalent protein adducts and other modification of cellular proteins or by induction of immune responses against its covalent protein adducts. However, the detailed mechanisms of idiosyncratic drug-induced liver injury (DILI) have been unclear. The objective is to clarify the involvement of DIC-AG and 4′hydroxydiclofenac (4′OH-DIC) in acute DILI. Methods: We examined the effects of inhibiting DIC-AG and 4′OH-DIC production on covalent protein adduct formation and lactate dehydrogenase leakage using sandwich-cultured rat hepatocytes (SCRHs). Results: After pretreatment of SCRH with (−)-borneol (BOR, a uridine diphosphate (UDP)-glucuronosyltransferase inhibitor) or sulfaphenazole (SUL, a cytochrome P450 2C9 inhibitor) for 30 minutes, intracellular concentrations of DIC, DIC-AG, and 4′OH-DIC were determined after further treating cells with 300 μM DIC for 3 hours. The decreased levels of reactive metabolites caused by BOR or SUL pretreatment resulted in decreased lactate dehydrogenase leakage from SCRH, although the formation of covalent protein adducts was not affected. Conclusion: These results suggested that both DIC-AG and 4′OH-DIC may be involved in acute cytotoxicity by DIC.
ISSN:1091-5818
1092-874X
DOI:10.1177/1091581817700584