Inhibition by phenyl N-tert-butyl nitrone of early phase carcinogenesis in the livers of rats fed a choline-deficient, L-amino acid-defined diet.
Male Wistar rats were fed a choline-deficient, L-amino acid-defined (CDAA) diet alone or in combination with a nitrone-based free radical trapping agent, phenyl N-tert-butyl nitrone (PBN) in the drinking water at the concentrations of 0.013, 0.065, and 0.130% for 12 weeks. PBN inhibited the changes that are normally induced in the livers of rats by the CDAA diet feeding, i.e., development of putative preneoplastic lesions, proliferation of connective tissue, reduction of glutathione S-transferase activity, formation of 8-hydroxyguanine in DNA, and an increase in inducible cyclo-oxygenase (COX2) activity. PBN, however, did not prevent the increases in the COX2 mRNA or protein levels brought on by the CDAA diet These results indicate that the loss of glutathione S-transferase activity and COX2 induction may play significant roles in rat liver carcinogenesis by the CDAA diet and that PBN prevents neoplasia not only by its radical scavenging activity but also by inhibiting COX2 activity at the catalytic level.
Nakae
D
D
Department of Oncological Pathology, Cancer Center, Nara Medical University, Kashihara, Japan. dnakae@nmu-gw.cc.naramed-u.ac.jp
Kotake
Y
Y
Kishida
H
H
Hensley
K L
KL
Denda
A
A
Kobayashi
Y
Y
Kitayama
W
W
Tsujiuchi
T
T
Sang
H
H
Stewart
C A
CA
Tabatabaie
T
T
Floyd
R A
RA
Konishi
Y
Y
D000596:Amino Acids / Q000172:deficiency*; D000818:Animals; D002796:Choline Deficiency / Q000150:complications*; D003497:Cyclic N-Oxides; D051546:Cyclooxygenase 2; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D007527:Isoenzymes / Q000187:drug effects; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D016328:NF-kappa B / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D009589:Nitrogen Oxides / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D000596:Amino Acids; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D007527:Isoenzymes; D016328:NF-kappa B; D009589:Nitrogen Oxides; C029217:phenyl-N-tert-butylnitrone; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D005978:Glutathione