Bilirubin inhibition of enzymes involved in the mitochondrial malate-aspartate shuttle.
The effect of increasing bilirubin concentrations upon the catalytic activity of a series of dehydrogenases and aminotransferases was examined. The particular enzymes were chosen to examine the effect of bilirubin upon the activity of enzymes responsible for the indirect transfer of reducing equivalents across the inner mitochondrial membrane. Malate dehydrogenase was inhibited at very low concentrations of bilirubin and showed competitive inhibition with respect to coenzyme of 2 microM, while the cytosolic form of this enzyme exhibited a 15 microM inhibition constant. Cytosolic glycerol-3-phosphate dehydrogenase was not appreciably inhibited by bilirubin. Both the mitochondrial and cytosolic forms of aspartate aminotransferase showed moderate competitive bilirubin inhibition with respect to substrates with a Ki of 30 microM with respect to 2-oxoglutarate and a Ki of 80 microM with respect to aspartate. Preincubation studies indicated that inhibition was reversible for all enzymes examined. These results are interpreted in terms of the inhibition of the malate-aspartate shuttle by relatively low concentrations of bilirubin.
D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism*; D001663:Bilirubin / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D003600:Cytosol / Q000201:enzymology; D007425:Intracellular Membranes / Q000187:drug effects; D008291:Malate Dehydrogenase / Q000037:antagonists & inhibitors; D008293:Malates / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors; D010084:Oxidation-Reduction; D000637:Transaminases / Q000037:antagonists & inhibitors
D008293:Malates; D001224:Aspartic Acid; D008291:Malate Dehydrogenase; D009247:NADH, NADPH Oxidoreductases; D000637:Transaminases; D001663:Bilirubin