digitonin and Leukemia-Lymphoma--Adult-T-Cell

Dihydroorotate dehydrogenase (DHODH) catalyzes the oxidation of dihydroorotate to orotate in the pyrimidine biosynthesis pathway. It is functionally connected to the respiratory chain, delivering electrons to ubiquinone. We report here that inhibition of cytochrome c oxidase by nitric oxide (NO) indirectly inhibits DHODH activity. In digitonin-permeabilized cells, DEA/NO, a chemical NO donor, induced a dramatic decrease in DHO-dependent O(2) consumption. The inhibition was reversible and more pronounced at low O(2) concentration; it was correlated with a decrease in orotate synthesis. Since orotate is the precursor of all pyrimidine nucleotides, indirect inhibition of DHODH by NO may significantly contribute to NO-dependent cytotoxicity.

Topics: Animals; Antioxidants; Ascorbic Acid; Digitonin; Dihydroorotate Dehydrogenase; Electron Transport; Electron Transport Complex IV; Enzyme Inhibitors; Humans; Hydrazines; K562 Cells; Leukemia L1210; Leukemia-Lymphoma, Adult T-Cell; Macrophages; Mice; Mitochondria; Nitric Oxide; Nitric Oxide Donors; Nitrogen Oxides; Orotic Acid; Oxidation-Reduction; Oxidoreductases; Oxidoreductases Acting on CH-CH Group Donors; Oxygen; Rats; Recombinant Proteins; Tumor Cells, Cultured