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Effect of Carnitine on Propionate Metabolism in the Vitamin B-12—Deficient Rat¹

Departments of Medicine and Pharmacology, Division of Clinical Pharmacology, University of Colorado Health Sciences Center, Denver, CO 80262

Acyl-CoA thioesters are generated during the oxidation of organic acids in mammalian systems. Vitamin B-12 deficiency is associated with decreased L-methylmalonyl-CoA mutase activity, and consequent accumulation of propionyl-CoA and methylmalonyl-CoA. The formation of propionyicamitine from propionyl-CoA and carnitine provides an alternative pathway to remove propionyl-CoA from cells. Hepatocytes isolated from vitamin B-12-deficient rats metabolized propionate (1 mM) to CO₂ and glucose at only 23% and 12%, respectively, of the rates observed in hepatocytes from control animals. In contrast, no difference was seen in rates of pyruvate metabolism by hepatocytes from control and vitamin B-12-deficient rats. Addition of carnitine (10 mM) to hepatocyte incubations increased the rate of propionylcarnitine formation 10- to 20-fold without altering conversion of propionate to CO₂ or glucose. The rate of propionylcarnitine formation was not affected by vitamin B-12 deficiency. When carnitine (10 mM) was added, proplonylcamitine generation represented 65–71% of total propionate utilization in hepatocytes isolated from vitamin B-12-deficient rats. Gluconeogenesis from [1-¹⁴C]pyruvate was inhibited by 1 mM propionate in hepatocytes from vitamin B-12-deficient rats. No effect of 1 mM propionate on glucose formation from pyruvate was seen using hepatocytes from control rats. Intraperitoneal administration of L-camitine resulted in a significant increase in urinary propionylcarnitine excretion from vitamin B-12-deficient rats, but not from control animals. The results demonstrate that exogenous camitine can significantly enhance propionyl-group utilization via the formation of acylcarnitines under the conditions of impaired acyl-CoA metabolism associated with vitamin B-12 deficiency.

KEY WORDS: • vitamin B-12 • carnitine • propionate • acylcamitine • pyruvate • hepatocytes • rat

¹ Supported by National Institutes of Health Grant DK 36069.

Manuscript received 3 January 1989. Revision accepted 30 March 1989.