ATP-generating glycolytic substrates prevent N-nitrosofenfluramine-induced cytotoxicity in isolated rat hepatocytes.

Abstract

The relationship between cytotoxicity induced by N-nitrosofenfluramine and mitochondrial or glycolytic adenosine triphosphate (ATP) synthesis-dependent intracellular bioenergetics was studied in isolated rat hepatocytes. The supplementation of fructose, an ATP-generating glycolytic substrate, to hepatocyte suspensions prevented N-nitrosofenfluramine-induced cell injury accompanied by the formation of cell blebs, abrupt loss of intracellular ATP and reduced glutathione and mitochondrial membrane potential (DeltaPsi), and the accumulation of oxidized glutathione and malondialdehyde, indicating lipid peroxidation, during a 2h incubation period. Fructose (1-20mM) resulted in concentration-dependent protection against the cytotoxicity of N-nitrosofenfluramine at a concentration of 0.6mM, a low toxic dose. Pretreatment with xylitol, another glycolytic substrate, at concentration of 15mM also prevented the cytotoxicity caused by the nitroso compound, but neither glucose nor sucrose exhibited protective effects. In addition, fructose inhibited N-nitrosofenfluramine (0.5 and 0.6mM)-induced DNA damage, as evaluated in the comet assay, indicating that nuclei as well as mitochondria are target sites of the compound. These results indicate that (a) the onset of N-nitrosofenfluramine-induced cytotoxicity in rat hepatocytes is linked to mitochondrial failure, and that (b) the insufficient supply of ATP in turn limits the activities of all energy-requiring reactions and consequently leads to acute cell death.

• Authors: Yoshio Nakagawa, Sumiko Tayama, Akio Ogata, Toshinari Suzuki, Hidemi Ishii
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 164 Issue 1-2 Pg. 93-101 (Dec 01 2006) ISSN: 0009-2797 [Print] Ireland
• PMID: 17056023 (Publication Type: Journal Article)

Chemical References

• nitrosofenfluramine
• Fenfluramine
• Adenosine Triphosphate
• Glutathione

Topics

• Adenosine Triphosphate (pharmacology)
• Animals
• Cell Death (drug effects)
• Cells, Cultured
• Comet Assay
• DNA Damage
• Dose-Response Relationship, Drug
• Fenfluramine (analogs & derivatives, metabolism, toxicity)
• Glutathione (metabolism)
• Glycolysis
• Hepatocytes (drug effects, metabolism)
• Male
• Membrane Potentials (drug effects, physiology)
• Mitochondria, Liver (drug effects, metabolism)
• Rats
• Rats, Inbred F344
• Time Factors