l-Carnitine delays the killing of cultured hepatocytes by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

The role of fatty acid metabolism in chemical-dependent cell injury is poorly understood. Addition of l-carnitine to the incubation medium of cultured hepatocytes delayed cell killing initiated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Protection by l-carnitine was stereospecific and observed as late as 1 h following addition of MPTP. d-Carnitine, but not iodoacetate, reversed the l-carnitine effect. Monoamine oxidase A and B activities, MPTP/N-methyl-4-phenylpyridinium levels, and MPTP-dependent loss of mitochondrial membrane potential measured by release of [³H]triphenylmethylphosphonium were not altered by addition of l-carnitine. Significant changes in MPTP-induced depletion of total cellular ATP did not occur with excess l-carnitine. Although the mechanism of cytoprotection exerted by l-carnitine remains unresolved, the data suggest that l-carnitine does not significantly alter: (i) mitochondrial-dependent bioactivation of MPTP; (ii) MPTP-dependent loss of mitochondrial membrane potential; or (iii) MPTP-mediated depletion of total cellular ATP content. We conclude that alterations of fatty acid metabolism may contribute to the toxic consequences of exposure to MPTP. Moreover, the lack of l-carnitine-mediated cytoprotection of monolayers incubated with 4-phenylpyridine or potassium cyanide suggests: (i) a link between fatty acid metabolism and mitochondrial membrane-mediated, bioactivation-dependent cell killing; and (ii) that inhibition of NADH dehydrogenase may not totally explain the mechanism of MPTP cytotoxicity.