PATHOPHYSIOLOGIC STUDY ON METHYLMALONIC ACIDURIA - DECREASE IN LIVER HIGH-ENERGY PHOSPHATE AFTER PROPIONATE LOADING IN RATS

Methylmalonate or propionate was i.v. infused into B12-deprived and control rats. In the B12-deprived rats, the plasma and liver concentrations of B12 decreased to 8 and 13%, respectively, of those of the control rats. The propionate loading produced a disproportionate increase in liver propionate levels; the mean ratio of methylmalonate to propionate in the liver was approximately 1.0 after methylmalonate loading, whereas it was 0.1 to 0.2 after propionate loading. The liver propionate and methylmalonate levels in the B12-deprived rats were twice as high as those in the control rats. The mean ratio of beta-ATP to inorganic phsophate in the liver, measured with P-31-magnetic resonance spectroscopy, decreased from 0.60 to 0.48 in the B12-deprived rats and from 0.78 to 0.63 in the control rats after methylmalonate loading; the ratio decreased from 0.57 to 0.37 in the B12-deprived rats and from 0.76 to 0.56 in the controls after propionate loading. Statistical analysis showed that propionate loading caused a more marked decrease in ATP than did methylmalonate loading (F = 26.33, degree of freedom 1 and 15; p < 0.001), while B12-deprivation caused a more marked decrease in ATP than did the control diet (F = 92.26, df1 and 15; p < 0.001). The concentrations of tricarboxylic acid cycle intermediates and related organic acids in the livers of the rats suggested that propionate inhibited NAD+-dependent enzymes in the cycle. These results indicate that propionate, which accumulates during crises in methylmalonic aciduria, contributes to the decrease in ATP levels to a greater extent than does methylmalonate, and thus impairs the ATP-dependent carboxylation of propionate itself to methylmalonate.