Effects of oxidative stress induced by redox-enzyme modulation on rat hepatocarcinogenesis

Toxicology Letters
A DendaY Konishi

Abstract

Inducibility of oxidative stress by menadione-associated redox cycling activation under redox-enzyme modulated conditions was examined in F344 male rat liver, by monitoring 8-hydroxydeoxyguanosine (8-OHdG) levels in DNA and hepatocyte injury. Further, the treatment-associated liver tumor-initiating, -promoting and -progressing potentials were assessed in terms of development of enzyme-altered preneoplastic foci, neoplastic nodules and hepatocellular carcinomas. With or without menadione, redox-enzyme modulation consisting of increased cytochrome P450 reductase by phenobarbital (PB), depletion of glutathione by phorone, inhibition of DT-diaphorase by dicumarol, with or without further supplement of iron, caused both 8-OHdG production and hepatocyte necrosis. Thus-induced oxidative stress exerted liver tumor promoting-activity in N-nitrosodiethylamine (DENA)-initiated rats, but neither initiating activity when promoted by 0.05% PB diet for 64 weeks, nor progressing activity when the oxidative stress was given for 33 weeks to preneoplastic nodule-bearing rats which was induced by DENA.

References

Jan 1, 1992·Pharmacology & Therapeutics·K Frenkel
Jan 1, 1991·Molecular Carcinogenesis·R W TennantR A Griesemer
Sep 1, 1991·Mutation Research·B N Ames, L S Gold
Sep 1, 1990·Carcinogenesis·R A Floyd
Jan 25, 1985·Science·P A Cerutti

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