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-mu-g/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 rat hepatocytes 17, 18. To learn more about the mechanism of human VPA induced hepatotoxicity the following in vitro study was conducted in which liver slices were prepared from either liver obtained from organ donors or from patients undergoing surgical liver resections. Human liver slices were treated with clinical doses of VPA in order to identify widely differing hepatotoxicity profiles produced19, 20, 21. Future studies will concentrate on correlating these differences with differences in intermediary metabolic status or VPA metabolism.