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Accumulation of methylmalonic acid caused by vitamin B12-deficiency disrupts normal cellular metabolism in rat liver

Published online by Cambridge University Press:  09 March 2007

Shigeki Toyoshima ,
Fumio Watanabe ,
Hisako Saido ,
Ewa H. Pezacka ,
Donald W. Jacobsens ,
Kazutaka Miyatake  and
Yoshihisa Nakano
Shigeki Toyoshima
Affiliation:
Department of Applied Biological Chemistry, Osaka Prefecture University, Sakai, Osaka 593, Japan
Fumio Watanabe
Affiliation:
Department of Foods and Nutrition, Kochi Women's University, Kochi 780, Japan
Hisako Saido
Affiliation:
Department of Applied Biological Chemistry, Osaka Prefecture University, Sakai, Osaka 593, Japan
Ewa H. Pezacka
Affiliation:
Departments of Cell Biology and Clinical Pathology, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
Donald W. Jacobsens
Affiliation:
Departments of Cell Biology and Clinical Pathology, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
Kazutaka Miyatake
Affiliation:
Department of Applied Biological Chemistry, Osaka Prefecture University, Sakai, Osaka 593, Japan
Yoshihisa Nakano
Affiliation:
Department of Applied Biological Chemistry, Osaka Prefecture University, Sakai, Osaka 593, Japan
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Abstract

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To clarify the relationship between intracellular concentrations of methylmalonic acid and metabolic and growth inhibition in vitamin B12-deficient rats, hepatic methylmalonic acidlevels were assayed and inhibition of glucose and glutamic acid metabolism by methylmalonic acid was studied in isolated hepatocytes. Vitamin B12-deficient rats (14 weeks old) excreted more urinary methylmalonic acid and had lower body weights than the control rats. Hepatic methylmalonic acid levels (3·6 (SD 1·30)–5·3 (SD 0·51) µmol/g tissue; 7·9 (SD 2·90)–11·8 (SD 1·14) mM) were increased and correlated with the extent of the growth retardation during vitamin B12-deficiency. Isolated hepatocytes and mitochondria from normally fed rats were labelled with [14C(U)]glucose and [14C(U)]glutamic acid respectively, in the presence or absence of 5mM-methylmalonic acid. Although methylmalonic acid did not affect the incorporation of 14C into protein and organic acid fractions in the hepatocytes, it inhibited 14CO2 formation (an index of glucose oxidation by the Krebs cycle) by 25% and incorporation of 14C into the amino acid fractionby 30%. In the mitochondria, methylmalonic acid inhibited 14CO2, formation (indicating glutamic acid oxidation by the Krebs cycle) by 70%, but not the incorporation of 14C into the protein fraction. The incorporation of 14C into the organic acid fraction was significantly stimulated by the addition of methylmalonic acid. These results indicate that the unusual accumulation of methylmalonic acid caused by vitamin B12-deficiency disrupts normal glucose and glutamic acid metabolism in rat liver, probably by inhibiting the Krebs cycle.

Keywords

Vitamin B12Methylmalonic acidLiver
Type
Cobalamin deficiency
Information
British Journal of Nutrition , Volume 75 , Issue 6 , June 1996 , pp. 929 - 938
Copyright
Copyright © The Nutrition Society 1996

References

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