DMD Simcyp

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

Drug Metabolism and Disposition Fast Forward
First published on November 12, 2008; DOI: 10.1124/dmd.108.024521

0090-9556/09/3702-345-351$20.00
DMD 37:345-351, 2009

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Data Supplement
Right arrow All Versions of this Article:
dmd.108.024521v1
37/2/345    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mizuno, K.
Right arrow Articles by Yokoi, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mizuno, K.
Right arrow Articles by Yokoi, T.

Metabolic Activation of Benzodiazepines by CYP3A4Formula

Katsuhiko Mizuno, Miki Katoh1, Hirotoshi Okumura, Nao Nakagawa, Toru Negishi, Takanori Hashizume, Miki Nakajima, and Tsuyoshi Yokoi

Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (K.M., M.K., H.O., N.N., M.N., T.Y.); and Pharmacokinetics Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan (T.N., T.H.)

Cytochrome P450 3A4 is the predominant isoform in liver, and it metabolizes more than 50% of the clinical drugs commonly used. However, CYP3A4 is also responsible for metabolic activation of drugs, leading to liver injury. Benzodiazepines are widely used as hypnotics and sedatives for anxiety, but some of them induce liver injury in humans. To clarify whether benzodiazepines are metabolically activated, 14 benzodiazepines were investigated for their cytotoxic effects on HepG2 cells treated with recombinant CYP3A4. By exposure to 100 µM flunitrazepam, nimetazepam, or nitrazepam, the cell viability in the presence of CYP3A4 decreased more than 25% compared with that of the control. In contrast, in the case of other benzodiazepines, the changes in the cell viability between CYP3A4 and control Supersomes were less than 10%. These results suggested that nitrobenzodiazepines such as flunitrazepam, nimetazepam, and nitrazepam were metabolically activated by CYP3A4, which resulted in cytotoxicity. To identify the reactive metabolite, the glutathione adducts of flunitrazepam and nimetazepam were investigated by liquid chromatography-tandem mass spectrometry. The structural analysis for the glutathione adducts of flunitrazepam indicated that a nitrogen atom in the side chain of flunitrazepam was conjugated with the thiol of glutathione. Therefore, the presence of a nitro group in the side chain of benzodiazepines may play a crucial role in the metabolic activation by CYP3A4. The present study suggested that metabolic activation by CYP3A4 was one of the mechanisms of liver injury by nitrobenzodiazepines.

Address correspondence to: Dr. Tsuyoshi Yokoi, Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakumamachi, Kanazawa 920-1192, Japan. E-mail: tyokoi{at}kenroku.kanazawa-u.ac.jp






Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2009 by the American Society for Pharmacology and Experimental Therapeutics.