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Hydroxycobalamin[c-lactam] Increases Total Coenzyme A Content in Primary Culture Hepatocytes by Accelerating Coenzyme A Biosynthesis Secondary to Acyl-CoA Accumulation^{1, 2,}

Departments of Medicine and Pharmacology, Division of Clinical Pharmacology, Case Western Reserve University, Cleveland, OH 44106-4981

Hydroxycobalamin[c-lactam] (HCCL) treatment in rats results in decreased hepatic L-methylmalonyl-CoA mutase activity and increased hepatic total CoA content. To test the hypothesis that HCCL increases hepatic CoA biosynthesis secondary to propionyl- and methylmalonyl-CoA accumulation, CoA homeostasis was studied in primary culture rat hepatocytes. Conversion of [¹⁴C]pantothenic acid to [¹⁴C]CoA in the primary culture system was accelerated to rates 3–5 times control by acute incubation with the acyl-CoA-generating carboxylic acids pivalate (10 mmol/L) or propionate (10 mmol/L). HCCL (1 mg/L included from 24 to 72 h of culture) had no affect on the distribution of the hepatocyte CoA pool or total CoA content. However, culture in the presence of HCCL and propionate (2 mmol/L) resulted in accumulation of methylmalonyl-CoA and a 59% increase in total CoA content. The combination of HCCL (1 mg/L) and propionate (0.5 mmol/L), but not HCCL alone, increased the rate of [¹⁴C]pantothenic acid conversion to [¹⁴C]CoA by 150%. Degradation of [¹⁴C]CoA in the primary culture hepatocyte system was unaffected by chronic exposure to 2 mmol/L propionate, but was increased 90% by the combination of HCCL and 2 mmol/L propionate. Thus, in the presence of a source of propionyl-CoA, HCCL treatment results in methylmalonyl-CoA accumulation and accelerated CoA biosynthesis. The increased CoA biosynthesis leads to increased hepatocyte total CoA content, which may contribute to cellular metabolic homeostasis under conditions of acyl-CoA accretion.

KEY WORDS: • cobalamin • coenzyme A • rats • propionate • hepatocyte

¹ Supported by grant DK36069 from the National Institutes of Health. Eric P. Brass is a Burroughs Wellcome Scholar in Clinical Pharmacology.

² The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.

Manuscript received 26 April 1993. Revision accepted 1 July 1993.