Hepatoxicity mitochondrial

Qu B., Q.-T. Li, K.P. Wong, T.M.C. Tan, and B. Halliwell (2001). Mechanisms of clofibrate hepatoxicity Mitochondrial damage and oxidative stress in hepatocytes. Free Radical Biology and Medicine 31 659-669. 

Kay P., P.A. Blackwell, and A.B.A. Boxall (2004). Pate of veterinary antibiotics in a macro-porous tile drained clay soil. Environmental Toxicology and Chemistry 23 1136-1144. Keller B.J., H. Yamanaka, and R.G. Thurman (1992). Inhibition of mitochondrial respiration and oxygen-dependent hepatoxicity by six structurally dissimilar peroxisomal proliferating agents. Toxicology 71 49-61. 

Valproic acid is rapidly distributed and the plasma protein binding is concentration dependent (18). As previously noted, valproic acid is extensively metabolized, primarily in the liver, with about 30-50% of the drug excreted as the glucuronide (phase II metabolism) in the urine, about 30-40%by the phase I mitochondrial j3-oxidation pathway, and about 10-20% by microsomal cytochrome P450-mediated hy droxylation/dehydrogena-tion of the side chain that provides the major phase I metabolites (36). The metabolites of valproic acid have been thought to be the cause of a rare, but fatal hepatotoxicity (35). The synthetic ( )-2,4-diene VPA has been shown to induce the same hepatic microve-sicular steatosis seen in patients, in chronic administration studies in rats (36). The ultimate causative factor (s) of hepatoxicity of valproic acid currently remain undefined (28,29). 

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