Decrease of flux through pyruvate dehydrogenase and branched-chain 2-oxo-acid dehydrogenase by nitrofurantoin in...

Addition of nitrofurantoin to isolated perfused rat liver leads to an inhibition of 14CO2 production from [1-14C]pyruvate, 2-oxo-[1-14C]isocaproate and 2-oxo-[1-14C]isovalerate, indicating a decreased flux through the corresponding mitochondrial 2-oxo-acid dehydrogenases. This is in agreement with a decreased tissue level of the active (dephospho)form of pyruvate dehydrogenase in presence of nitrofurantoin. 2) Evidence is presented for an inhibition of the monocarboxylate translocator in the mitochondrial membrane during addition of nitrofurantoin by comparing the effects of alpha-cyanocinnamate as a transport inhibitor with those of nitrofurantoin. 3) It is concluded that nitrofurantoin-induced hepatocyte toxicity may include mitochondrial effects due to decreased oxo-acid dehydrogenase flux.