EXPERIMENTAL STUDY ON ANTIOXIDANTS AND L-CARNITINE PREVENTING HEPATOTOXICITY INDUCED BY VALPROIC ACID IN DIFFERENT AGE RATS

Objectives: To explore the age difference of hepatotoxicity induced by valproic acid (VPA) in rats and the capability of L-carnitine and antioxidants preventing the side effect.

Methods: 32 infant (21 days) and 32 adult Wistar rats were divided into 4 groups (n=8) respectively and administrated orally as follows: (1) T0i and T0a (control groups) were given with normal saline. (2) T1i and T1a were treated with VPA (500mg/kg/day) keeping its serum concentration within 52 to 87.7ug/ml. (3) T2i and T2a were coadministrated with VPA and L-carnitine (200mg/kg/day). (4) In T3i and T3a, VPA were coadministrated with two antioxidants, VitE (100mg/kg/day) and CoQ10 (20mg/kg/day). All rats were sacrificed 30 days later. Morphology of hepatocytes was observed by H&E and Oil-Red-O staining. The quantities of cytochrome aa3, activities of succinic dehydrogenase (SDH) and cytochrome oxidase (CCO) in liver mitochondria were detected by chromatometry.

Results: (1) The numbers of hepatocytes containing lipid droplets were dominantly increased in T1i and T1a, infant rats were more significant than adults (P<0.01), but no significant increase in T2i, T2a, T3i and T3a. (2) The reduction of cytochrome aa3 quantities and CCO activities was notable in both T1i and T1a (P<0.01), activities of SDH decreased by 44.8% (P<0.01) in T1i but normal in T1a. (3) Comparing to the control, there was no significant difference of cytochrome aa3, SDH and CCO in T3i and T3a, and neither in T2i and T2a except cytochrome aa3.

Conclusion: (1) Mitochondrial dysfunction of hepatocytes plays a causative role in VPA associated liver failure and infant rats are more susceptible. (2) Supplying L-carnitine, VitE and CoQ10 could effectively prevent this side effect.