Fructose prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced ATP depletion and toxicity in isolated hepatocytes

Abstract

The loss of viability of isolated rat hepatocytes exposed to either 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or its toxic metabolite 1-methyl-4-phenylpyridinium ion (MPP+) was prevented by addition of fructose to the incubation medium. This protection was dependent on fructose concentration, being complete at 10 mM. Addition of fructose dramatically delayed MPTP- and MPP+-induced depletion of ATP and was accompanied by a significant accumulation of lactate, indicating the occurrence of enhanced glycolytic production of ATP. Glucose was much less effective against MPTP and MPP+ toxicity, probably because it is a relatively poor substrate for glycolysis in liver cells. We conclude that depletion of ATP is a critical event in MPTP cytotoxicity in our in vitro model system, and that the use of alternative sources of ATP production may represent an important protective device against the effects of this toxic agent.