Effects of phenyl N-tert-butyl nitrone and its derivatives on the early phase of hepatocarcinogenesis in rats fed a choline-deficient, L-amino acid-defined diet.
The present study examined the effects of various derivatives of a radical trapping agent, phenyl N-tert-butyl nitrone, on the early phase of hepatocarcinogenesis in male Wistar rats fed a choline-deficient, L-amino acid-defined diet for 16 weeks. The derivatives used were 4-hydroxyphenyl (a physiologically major metabolite), 3-hydroxyphenyl, 2-hydroxyphenyl and 2-sulfoxyphenyl N-tert-butyl nitrone, and their effects were studied in a comparison with those of the parent compound, phenyl N-tert-butyl nitrone. The sizes of putatively preneoplastic, glutathione S-transferase placental form-positive lesions and the levels of extra-nuclear oxidative injury of hepatocytes, using the formation of 2-thiobarbituric acid-reacting substances as a parameter, were decreased by all doses (0.009%, 0.045% and 0.090% in diet) of 4-hydroxyphenyl N-tert-butyl nitrone and only by the highest dose of 3-hydroxyphenyl N-tert-butyl nitrone and phenyl N-tert-butyl nitrone. While 4-hydroxyphenyl N-tert-butyl nitrone, 3-hydroxyphenyl N-tert-butyl nitrone and phenyl N-tert-butyl nitrone all enhanced and inhibited hepatocellular apoptosis in preneoplastic lesions and their surrounding tissue, respectively, only 4-hydroxyphenyl N-tert-butyl nitrone additionally inhibited hepatocyte proliferation both in preneoplastic lesions and their surrounding tissue. 2-Hydroxyphenyl or 2-sulfoxyphenyl N-tert-butyl nitrone did not exert any of the above effects. These results suggest that the selective induction of apoptosis in preneoplastic hepatocyte populations plays a crucial role in the inhibition of hepatocarcinogenesis derived by phenyl N-tert-butyl nitrone and its effective derivatives. Further, the metabolic conversion to 4-hydroxyphenyl N-tert-butyl nitrone may also be important for the inhibitory effects of phenyl N-tert-butyl nitrone on hepatocarcinogenesis.
Nakae
Dai
D
Department of Pathology, Sasaki Institute, Sasaki Foundation, 2-2 Kanda-Surugadai, Chiyoda, Tokyo 101-0062. dai.nakae@sasaki.or.jp
Kishida
Hideki
H
Enami
Tomonori
T
Konishi
Yoichi
Y
Hensley
Kenneth L
KL
Floyd
Robert A
RA
Kotake
Yashige
Y
D000596:Amino Acids / Q000008:administration & dosage*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000032:analysis; D002455:Cell Division / Q000187:drug effects; D002796:Choline Deficiency / Q000150:complications*; D003497:Cyclic N-Oxides; D004305:Dose-Response Relationship, Drug; D005234:Fatty Liver / Q000188:drug therapy / Q000209:etiology; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use*; D005982:Glutathione Transferase / Q000032:analysis; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000209:etiology; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D015394:Molecular Structure; D009589:Nitrogen Oxides / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress; D011230:Precancerous Conditions / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
D000596:Amino Acids; D016588:Anticarcinogenic Agents; D014408:Biomarkers, Tumor; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D009589:Nitrogen Oxides; C029217:phenyl-N-tert-butylnitrone; D005982:Glutathione Transferase