Induction of 8-hydroxydeoxyguanosine but not initiation of carcinogenesis by redox enzyme modulations with or without menadione in rat liver.
Inducibility of oxidative stress in rat liver in vivo by menadione-associated redox cycling activation under redox enzyme modulating conditions was examined by monitoring hepatocyte injury and 8-hydroxydeoxyguanosine (8-OHdG) levels of liver DNA. In addition, the treatment-associated liver tumor initiating activity was assessed in terms of development of gamma-glutamyl-transpeptidase (GGT)- and glutathione S-transferase placental form (GST-P)-positive foci and hyperplastic nodules. With or without following menadione treatment (50 mg/kg, i.g.), redox enzyme modulations of increased cytochrome P450 reductase activity induced by phenobarbital (PB)-Na (100 mg/kg, i.p. for 5 days), inhibition of DT-diaphorase by dicumarol (25 mg/kg, i.p.) and depletion of glutathione by phorone (200 mg/kg, i.p.), with or without further supplement of iron EDTA-Na-Fe(III) (70 mg/kg, i.p.), caused both substantial hepatocyte necrosis and 8-OHdG production in Fischer 344 male rats. Subsequent feeding with a 0.05% PB diet for 64 weeks resulted in slightly increased development of GGT-positive foci but not GST-P positive lesions or hyperplastic nodules, suggesting a lack of tumor-initiating activity of the oxidative DNA damage associated with redox enzyme modulations with or without menadione.
Denda
A
A
Department of Oncological Pathology, Cancer Center, Nara Medical College, Japan.
Sai
K M
KM
Tang
Q
Q
Tsujiuchi
T
T
Tsutsumi
M
M
Amanuma
T
T
Murata
Y
Y
Nakae
D
D
Maruyama
H
H
Kurokawa
Y
Y
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003579:Cytochrome Reductases / Q000096:biosynthesis / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D001728:Dicumarol / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D007659:Ketones / Q000494:pharmacology; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000209:etiology / Q000378:metabolism; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone); D009336:Necrosis; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000209:etiology / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology; D011808:Quinone Reductases / Q000037:antagonists & inhibitors; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D014812:Vitamin K / Q000494:pharmacology*; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D007659:Ketones; D014812:Vitamin K; D001728:Dicumarol; D000080242:8-Hydroxy-2'-Deoxyguanosine; C018637:phorone; D004247:DNA; D007501:Iron; D003579:Cytochrome Reductases; D016660:NAD(P)H Dehydrogenase (Quinone); D011808:Quinone Reductases; D005723:gamma-Glutamyltransferase; D003849:Deoxyguanosine; D005978:Glutathione; D010634:Phenobarbital