Hydroxycobalamin[c-lactam] increases total coenzyme A content in primary culture hepatocytes by accelerating coenzyme A biosynthesis secondary to Acyl-CoA accumulation.
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.
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Department of Medicine, Case Western Reserve University, Cleveland, OH 44106-4981.
D000214:Acyl Coenzyme A / Q000378:metabolism*; D000818:Animals; D001673:Biodegradation, Environmental; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D003065:Coenzyme A / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010205:Pantothenic Acid / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014805:Vitamin B 12 / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D000214:Acyl Coenzyme A; D002250:Carbon Radioisotopes; C071541:hydroxycobalamin(c-lactam); D010205:Pantothenic Acid; D014805:Vitamin B 12; D003065:Coenzyme A