Valproic acid hepatotoxicity in human liver slices.
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.
Fisher
R
R
Department of Pharmacology, University of Arizona, Tucson.
Nau
H
H
Gandolfi
A J
AJ
Putnam
C W
CW
Brendel
K
K
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011188:Potassium / Q000032:analysis; D014635:Valproic Acid / Q000633:toxicity*
D014635:Valproic Acid; D007770:L-Lactate Dehydrogenase; D011188:Potassium