Indirect inhibition of mitochondrial dihydroorotate dehydrogenase activityby nitric oxide

Dihydroorotate dehydrogenase (DHODH) catalyzes the oxidation of dihydroorot ate to orotate in the pyrimidine biosynthesis pathway. It is functionally c onnected to the respiratory chain, delivering electrons to ubiquinone. We r eport here that inhibition of cytochrome c oxidase by nitric oxide (NO) ind irectly inhibits DHODH activity. In digitonin-permeabilized cells, DEA/NO, a chemical NO donor, induced a dramatic decrease in DHO-dependent O-2 consu mption. The inhibition was reversible and more pronounced at low O-2 concen tration; it was correlated with a decrease in orotate synthesis. Since orot ate is the precursor of all pyrimidine nucleotides, indirect inhibition of DHODH by NO may significantly contribute to NO-dependent cytotoxicity. (C) 2000 Elsevier Science Inc.