Document Detail

Valproic acid hepatotoxicity in human liver slices.
MedLine Citation:
PMID:  1811959     Owner:  NLM     Status:  MEDLINE    
Precision cut human liver slices were incubated in organ culture with valproic acid (VPA) to identify patterns of sensitivity to VPA-induced hepatotoxicity. The slices were incubated in Krebs-HEPES buffer supplemented with 25mM glucose and 84 micrograms/ml gentamycin. At 2, 4, 6, 12, 18 and 24 hr slices were taken and analyzed for K+ retention, synthesis of protein and LDH leakage. All three of these viability indicators showed that certain human livers were more susceptible to VPA-induced hepatotoxicity than others. In the limited group of human livers investigated (n = 9) we found one to be particularly sensitive and two relatively insensitive to VPA toxicity. The remaining tissues were of intermediate sensitivity towards VPA. At this time there is no correlation between the human livers that were susceptible to VPA induced hepatotoxicity and age or sex. This study was designed to show that VPA does induce hepatotoxicity in vitro at therapeutically relevant concentrations. Future studies will show whether VPA hepatotoxicity correlates with VPA metabolism, nutritional status or concomitant therapy.
R Fisher; H Nau; A J Gandolfi; C W Putnam; K Brendel
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Drug and chemical toxicology     Volume:  14     ISSN:  0148-0545     ISO Abbreviation:  Drug Chem Toxicol     Publication Date:  1991  
Date Detail:
Created Date:  1992-06-10     Completed Date:  1992-06-10     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  7801723     Medline TA:  Drug Chem Toxicol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  375-94     Citation Subset:  IM    
Department of Pharmacology, University of Arizona, Tucson.
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MeSH Terms
Child, Preschool
Culture Techniques
Dose-Response Relationship, Drug
L-Lactate Dehydrogenase / metabolism
Liver / chemistry,  drug effects*,  metabolism
Middle Aged
Potassium / analysis
Valproic Acid / toxicity*
Grant Support
Reg. No./Substance:
7440-09-7/Potassium; 99-66-1/Valproic Acid; EC Dehydrogenase

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