Effect of hydroxycobalamin[c-lactam] on propionate and carnitine metabolism in the rat.
The administration in vivo of the cobalamin analogue hydroxycobalamin[c-lactam] inhibits hepatic L-methylmalonyl-CoA mutase activity. The current studies characterize in vivo and in vitro the hydroxycobalamin[c-lactam]-treated rat as a model of disordered propionate and methylmalonic acid metabolism. Treatment of rats with hydroxycobalamin[c-lactam] (2 micrograms/h by osmotic minipump) increased urinary methylmalonic acid excretion from 0.55 mumol/day to 390 mumol/day after 2 weeks. Hydroxycobalamin[c-lactam] treatment was associated with increased urinary propionylcarnitine excretion and increased short-chain acylcarnitine concentrations in plasma and liver. Hepatocytes isolated from cobalamin-analogue-treated rats metabolized propionate (1.0 mM) to CO2 and glucose at rates which were only 18% and 1% respectively of those observed in hepatocytes from control (saline-treated) rats. In contrast, rates of pyruvate and palmitate oxidation were higher than control in hepatocytes from the hydroxycobalamin[c-lactam]-treated rats. In hepatocytes from hydroxycobalamin[c-lactam]-treated rats, propionylcarnitine was the dominant product generated from propionate when carnitine (10 mM) was present. The addition of carnitine thus resulted in a 4-fold increase in total propionate utilization under these conditions. Hepatocytes from hydroxycobalamin[c-lactam]-treated rats were more sensitive than control hepatocytes to inhibition of palmitate oxidation by propionate. This inhibition of palmitate oxidation was partially reversed by addition of carnitine. Thus hydroxycobalamin[c-lactam] treatment in vivo rapidly causes a severe defect in propionate metabolism. The consequences of this metabolic defect in vivo and in vitro are those predicted on the basis of propionyl-CoA and methylmalonyl-CoA accumulation. The cobalamin-analogue-treated rat provides a useful model for studying metabolism under conditions of a metabolic defect causing acyl-CoA accretion.
Brass
E P
EP
Department of Medicine, University of Colorado Health Sciences Center, Denver 80262.
Allen
R H
RH
Ruff
L J
LJ
Stabler
S P
SP
D000214:Acyl Coenzyme A; D000818:Animals; D002331:Carnitine / Q000378:metabolism*; D006879:Hydroxocobalamin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007769:Lactams / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008314:Malonates / Q000652:urine; D008316:Malonyl Coenzyme A / Q000378:metabolism; D011422:Propionates / Q000378:metabolism*; D051381:Rats; D014806:Vitamin B 12 Deficiency / Q000378:metabolism
D000214:Acyl Coenzyme A; D007769:Lactams; D008314:Malonates; D011422:Propionates; C015357:methylmalonyl-coenzyme A; D008316:Malonyl Coenzyme A; C005230:methyl malonate; D006879:Hydroxocobalamin; D002331:Carnitine