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Alterations in cellular intermediary metabolism by 4-dimethylaminophenol in the isolated perfused rat liver and the implications for 4-dimethylaminophenol toxicity

1980; Elsevier BV; Volume: 29; Issue: 12 Linguagem: Inglês

10.1016/0006-2952(80)90135-5

1873-2968

Rembert Elbers, Sibylle Soboll, Hermann Kampffmeyer,

Genomics, phytochemicals, and oxidative stress

To evaluate the influence of 4-dimethylaminophenol (DMAP) on cellular intermediary metabolism, isolated rat livers were single pass perfused with subtoxic (0.3 mM) and toxic (1 mM) concentrations of DMAP. The rate of glycolysis and oxygen consumption both increased with biphasical kinetics immediately after the onset of DMAP infusion. After a transient reduction, the cytosolic NAD system was oxidized by DMAP; the mitochondrial NAD system, except for a brief initial oxidation, remained almost unaffected. DMAP caused an intracellular alkalinization. At 0.3 mM, this alkalinization was confined to the cytosol (+0.6pH units); at 1 mM the mitochondria were alkalized in addition (+0.8pH units). In freeze-clamped and lyophilized tissue, following 0.3mM DMAP, the ATP/ADP ratio was lowered by two-thirds and 2-oxoglutarate decreased by one-half; citrate, malate and the sum of adenine nucleotides were unchanged. After 1 mM DMAP, all metabolites were decreased, the ATP/ADP ratio was lowered by three-quarters. Subcellular fractionation revealed inhibition of the citric acid cycle by DMAP, resulting in lowered mitochondrial/cytosolic gradients for Krebs cycle intermediates. The cellular content of CoA was unchanged at 0.3 mM but diminished by 65 per cent at 1 mM, in accordance with the unchanged rate of ketogenesis at 0.3 mM and inhibition at 1 mM. We conclude that mitochondrial CoA depletion with subsequent inhibition of the citric acid cycle and of oxidative energy metabolism suffices to explain DMAP toxicity.