ISPO

Possible cytotoxic effects of lipophilic o-naphthoquinones in isolated rat hepatocytes; protective mechanisms.

M. Dubin , S. H. Fern√°ndez Villamil, N. De Witte, P. Carrizo, M.P. Molina Portela, A.O.M. Stoppani

Bioenergetics Research Centre, School of Medicine, University of Buenos Aires, Argentine.

β-Lapachone, a lipophilic o-naphthoquinone, exerts cytotoxic effects on many human tumor cells, inducing apoptosis or necrosis. A structurally related naphthoquinone, such as CG 10-248 (CG-NQ), is also effective on tumor cells and viruses but their action on normal cells has not been fully investigated. In order to characterize possible harmful effects in the host, that may prevent therapeutic use of CG-NQ as anti-tumor agent, we assayed its action on isolated rat hepatocytes and subcellular fractions obtained therefrom. After 5-15 min of hepatocyte incubation with 100 µM CG-NQ, significant effects were (a) decreased in NAD+, NADH and NADPH levels; (b) increased in NADP+ level; (c) decreased in GSH and increased in GSSG levels; (d) inhibition of lipid peroxidation; (e) increased hepatocyte respiration rate. After 1 hour incubation of hepatocytes with CG-NQ, no significant changes of cell viability were observed. Catalase and GSH-peroxidase activities were not modified. Examination of CG-NQ redox cycling in hepatocytes, mitochondria, and cytosol, demonstrated the quinone redox cycling and production of reactive oxygen species. These reactions would depend on flavoenzymes, such as diaphorase, mitochondrial and microsomal NAD(P)H:dehydrogenases. CG-NQ uncoupled oxidative phosphorylation, activated F0F1-ATP synthase and decreased mitochondrial membrane potential. However, detoxifying mechanisms, including GSH-dependent reactions, diaphorase and catalase would prevent CG-NQ cytotoxicity in intact hepatocytes.

For more information, contact stoppani@mail.retina.ar

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Apoptosis - Molecular Mechanisms.

http://www.cancerprev.org/Journal/Issues/26/101/1092/4321