Carnitine interacts with the metabolically active coenzyme A pool through the formation of acylcarnitines from acyl-CoAs. Recently, carnitine has been reported to have clinical efficacy in the treatment of hereditary organic acidemias and a number of other pathological conditions. The mechanism for these effects are presumed to be the generation of acylcarnitines and consequent alterations in cellular intermediary metabolism. However, proof of the mechanism is lacking, and fundamental information on the dynamics of acylcarnitine generation and its relationship to oxidative metabolism are needed. This proposal tests the hypothesis that acylcarnitine formation provides a mechanism for maintaining normal hepatic metabolism under conditions which acyl-CoAs accumulate and may impair liver metabolism. Vitamin B12 deficiency in rats will be used as a model. During vitamin B12 deficiency propionyl-CoA and methylmalonyl-CoA accumulate secondary to impaired methylmalonyl-CoA utilization. This situation is directly analogous to methylmalonic acidemia. During the development of vitamin B12 deficiency the plasma, urine and liver carnitine pools as well as total body carnitine content will be studied. Generation of acylcarnitines, particularly propionylcarnitine and methylmalonylcarnitine, will be monitored. Attention will be paid to possible secondary carnitine deficiency thought to develop clinically from increased acylcarnitine excretion. The liver CoA pool will also be quantitated and directly correlated to changes in the carnitine pool. Exogenous carnitine will be administered, and the response of the carnitine and CoA pools determined. Studies will also be done in isolated hepatocytes from vitamin B12 deficient rats. Acylcarnitine formation and alterations in the CoA pool will be determined in the hepatocyte and correlated with carnitine-induced changes in the hepatocytes' ability to oxidize pyruvate and palmitate. These studies will provide insight into how carnitine's interaction with the CoA pool may perturb hepatic metabolism and how acylcarnitine formation may improve hepatocellular function. The work proposed will also provide a rational basis for extended in vitro and in vivo studies of carnitine's effect on metabolism in disease states.
| Brass, E P; Beyerinck, R A (1987) Interactions of propionate and carnitine metabolism in isolated rat hepatocytes. Metabolism 36:781-7 |
| Brass, E P (1986) Effect of alpha-ketobutyrate on palmitic acid and pyruvate metabolism in isolated rat hepatocytes. Biochim Biophys Acta 888:18-24 |
| Brass, E P; Fennessey, P V; Miller, L V (1986) Inhibition of oxidative metabolism by propionic acid and its reversal by carnitine in isolated rat hepatocytes. Biochem J 236:131-6 |
