CARNITINE-DEPENDENT METABOLISM AND AMMONIA TOXICITY

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Cirrhosis of the liver is a common disease in which hepatic perfusion is compromised and parenchymal cells are progressively damaged and eventually destroyed. As hepatic function is lost, severe derangements of the central nervous system (CNS) also occur (hepatic encephalopathy). Available therapies are limited, and the long-term prognosis is poor. The CNS effects are believed to represent an intoxication of the brain by compounds normally removed from plasma by the liver. Although many compounds may contribute to the observed encephalopathy, there is abundant evidence that ammonia is a major toxin. S. Grisolia et al. recently reported that ammonia is much less toxic to mice previously given L-carnitine, a mitochondrial transport carrier for long-chain fatty acids. The protective mechanism is unknown. Studies of the biochemical basis for the protective effect of L-carnitine will focus on two questions: (1) Does L-carnitine, given at a protective dose, cross the blood-brain barrier in amounts sufficient to account for its effect on ammonia toxicity? The brain uptake index (BUI) for L-carnitine will be determined in rats. The BUI will then be altered pharmacologically, and the changes in BUI will be correlated with changes in ammonia toxicity, if any. The studies will indicate if the carnitine effect occurs peripherally or within the CNS; related studies will elucidate the metabolic role of carnitine in brain. (2) What is the mechanism by which carnitine alters ammonia toxicity? Carnitine stimulates fatty acid oxidation and thus increases intramitochondrial acety-CoA synthesis and, ultimately, ATP formation. Increased ATP levels may protect the CNS from ammonia toxicity directly or may stimulate hepatic urea formation and thus decrease plasma ammonia levels. By stimulating ketone body formation carnitine could also increase CNS energy sources and may thereby spare glucose carbon for glutamine synthesis. Alternatively, by stimulating branched-chain amino acid use in muscle carnitine may increase glutamine formation and decrease plasma ammonia levels. These hypotheses (and possibly others) will be investigated in vitro and in vivo using potent and specific inhibitors of key enzymes required for the hypothesized carnitine effect. Administration of such inhibitors should diminish the protective effect of carnitine if the blocked pathway is important. Several of the required inhibitors have been developed in previous unrelated studies; others are proposed in the application.