The combustion of alcohol and its inhibition by 4-methyl-pyrazole in perfused rat livers |
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Authors: | H Theorell B Chance T Yonetani N Oshino |
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Affiliation: | Medicinska Nobelinstitute, Biokemiska Avdelningen, Karolinska Institute, Solnavagen 1, 10401 Stockholm 60, Sweden;Johnson Research Foundation, University of Pennsylvania, Medical School, Philadelphia, Pennsylvania 19104, USA |
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Abstract: | Observation of the redox states of intracellular respiratory components localized in cell organelles affords a new approach to the study of ethanol metabolism in the hemoglobin-free perfused liver. Spectrophotometric observations of the catalase-H2O2 intermediate in the peroxisomes, and of cytochrome c in the mitochondria, are coupled with fluorometric observations of oxidized flavoprotein in the mitochondria and reduced pyridine nucleotide (NADH) in the mitochondrial and cytosolic spaces. The results demonstrate the effect of ethanol upon the intracellular redox poise and on the concentration of the catalase-H2O2 intermediate and, the specific effect of 4-methyl pyrazole (4-Me-pyrazole)2 upon the mitochondrial and cytosolic redox states. Ethanol decreases the concentration of the catalase-H2O2 intermediate, half-maximal effect being attained at 0.5 – 0.6 mm ethanol with endogenous substrate for the substrate-free perfusion of liver from fed rats at 30 °C. Simultaneously pyridine nucleotide and flavoprotein are half-maximally reduced at 0.4 – 0.5 mm ethanol. Cytochrome c is not significantly affected. 4-Me-pyrazole inhibits the responses of NADH and flavoprotein in a reaction that is competitive with ethanol at a ratio of ethanol to 4-Me-pyrazole of 3300:1 for 50% inhibition. The extrapolated Ki is 2 μm 4-Mepyrazole at zero ethanol. The responses to 4-Me-pyrazole are dependent in a complex manner upon the metabolic state of the liver, as demonstrated by the effect of octanoate, indicating that appropriate control of the cytosolic redox state of the perfused liver by 4-Me-pyrazole in the presence of ethanol requires a detailed knowledge of the many factors that poise the metabolic state of the organ in the perfused or intact condition. |
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