Valproic acid hepatotoxicity in human liver slices

Robyn Fisher, Heinz Nau, A Jay Gandolfi, Charles W. Putnam, Klaus Brendel

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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 μg/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.

Original languageEnglish (US)
Pages (from-to)375-394
Number of pages20
JournalDrug and Chemical Toxicology
Volume14
Issue number4
DOIs
StatePublished - 1991

Fingerprint

Valproic Acid
Liver
Acids
HEPES
Organ Culture Techniques
Gentamicins
Nutritional Status
Metabolism
Glucose
Toxicity
Buffers
Tissue
Proteins

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology
  • Health, Toxicology and Mutagenesis
  • Public Health, Environmental and Occupational Health
  • Chemical Health and Safety
  • Chemistry(all)

Cite this

Valproic acid hepatotoxicity in human liver slices. / Fisher, Robyn; Nau, Heinz; Gandolfi, A Jay; Putnam, Charles W.; Brendel, Klaus.

In: Drug and Chemical Toxicology, Vol. 14, No. 4, 1991, p. 375-394.

Research output: Contribution to journalArticle

Fisher, Robyn ; Nau, Heinz ; Gandolfi, A Jay ; Putnam, Charles W. ; Brendel, Klaus. / Valproic acid hepatotoxicity in human liver slices. In: Drug and Chemical Toxicology. 1991 ; Vol. 14, No. 4. pp. 375-394.
@article{6b6350a8c10b4802b0ef2ae9fce19328,
title = "Valproic acid hepatotoxicity in human liver slices",
abstract = "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 μg/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.",
author = "Robyn Fisher and Heinz Nau and Gandolfi, {A Jay} and Putnam, {Charles W.} and Klaus Brendel",
year = "1991",
doi = "10.3109/01480549109011640",
language = "English (US)",
volume = "14",
pages = "375--394",
journal = "Drug and Chemical Toxicology",
issn = "0148-0545",
publisher = "Informa Healthcare",
number = "4",

}

TY - JOUR

T1 - Valproic acid hepatotoxicity in human liver slices

AU - Fisher, Robyn

AU - Nau, Heinz

AU - Gandolfi, A Jay

AU - Putnam, Charles W.

AU - Brendel, Klaus

PY - 1991

Y1 - 1991

N2 - 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 μg/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.

AB - 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 μg/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.

UR - http://www.scopus.com/inward/record.url?scp=0026355132&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0026355132&partnerID=8YFLogxK

U2 - 10.3109/01480549109011640

DO - 10.3109/01480549109011640

M3 - Article

VL - 14

SP - 375

EP - 394

JO - Drug and Chemical Toxicology

JF - Drug and Chemical Toxicology

SN - 0148-0545

IS - 4

ER -