Document Detail

Involvement of cytochrome P450-mediated metabolism in tienilic acid hepatotoxicity in rats.
MedLine Citation:
PMID:  18992796     Owner:  NLM     Status:  MEDLINE    
Tienilic acid is reported to be converted into electrophilic metabolites by cytochrome P450 (CYP) in vitro. In vivo, however, the metabolites have not been detected and their effect on liver function is unknown. We previously demonstrated that tienilic acid decreased the GSH level and upregulated genes responsive to oxidative/electrophilic stresses, such as heme oxygenase-1 (Ho-1), glutamate-cysteine ligase modifier subunit (Gclm) and NAD(P)H dehydrogenase quinone 1 (Nqo1), in rat liver, as well as inducing hepatotoxicity by co-treatment with the glutathione biosynthesis inhibitor l-buthionine-(S,R)-sulfoximine (BSO). In this study, for the first time, we identified a glutathione-tienilic acid adduct, a stable conjugate of putative electrophilic metabolites with glutathione (GSH), in the bile of rats given a single oral dose of tienilic acid (300mg/kg). Furthermore, a tienilic acid-induced decrease in the GSH level and upregulation of Ho-1, Gclm and Nqo1 were completely blocked by pretreatment with the CYP inhibitor 1-aminobenzotriazole (ABT, 66mg/kg, i.p.). The increase in the serum ALT level and hepatocyte necrosis resulting from the combined dosing of BSO and tienilic acid was prevented by ABT, despite a low hepatic GSH level. These findings suggest that the electrophilic metabolites of tienilic acid produced by CYP induce electrophilic/oxidative stresses in the rat liver and this contributes to the hepatotoxicity of tienilic acid under impaired GSH biosynthesis.
Takayoshi Nishiya; Michiyuki Kato; Takami Suzuki; Chikako Maru; Hiroko Kataoka; Chiharu Hattori; Kazuhiko Mori; Toshimasa Jindo; Yorihisa Tanaka; Sunao Manabe
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Publication Detail:
Type:  Journal Article     Date:  2008-11-01
Journal Detail:
Title:  Toxicology letters     Volume:  183     ISSN:  0378-4274     ISO Abbreviation:  Toxicol. Lett.     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2008-12-01     Completed Date:  2009-03-30     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  7709027     Medline TA:  Toxicol Lett     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  81-9     Citation Subset:  IM    
Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 16-13 Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan.
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MeSH Terms
Administration, Oral
Antihypertensive Agents / administration & dosage,  chemistry,  toxicity
Apoptosis / drug effects
Bile / chemistry,  metabolism
Chromatography, Liquid / methods
Cytochrome P-450 Enzyme System / metabolism*
Drug-Induced Liver Injury
Gene Expression Profiling
Glutamate-Cysteine Ligase / genetics
Glutathione / metabolism
Heme Oxygenase-1 / genetics
Liver / drug effects*,  metabolism,  pathology
Liver Diseases / genetics,  metabolism*
Molecular Structure
NAD(P)H Dehydrogenase (Quinone) / genetics
RNA, Messenger / genetics,  metabolism
Rats, Sprague-Dawley
Reverse Transcriptase Polymerase Chain Reaction
Tandem Mass Spectrometry / methods
Ticrynafen / administration & dosage,  chemistry,  toxicity*
Up-Regulation / drug effects,  genetics
Reg. No./Substance:
0/Antihypertensive Agents; 0/RNA, Messenger; 40180-04-9/Ticrynafen; 70-18-8/Glutathione; 9035-51-2/Cytochrome P-450 Enzyme System; EC Oxygenase-1; EC Dehydrogenase (Quinone); EC Ligase

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