Effects of oxidative stress induced by redox-enzyme modulation on rat hepatocarcinogenesis.
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.
Denda
A
A
Department of Oncological Pathology, Nara Medical University, Japan.
Endoh
T
T
Nakae
D
D
Konishi
Y
Y
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000209:etiology*; D008297:Male; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D051381:Rats; D011916:Rats, Inbred F344
D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine