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Inhibition by Phenyl N-tert-Butyl Nitrone of Early Phase Carcinogenesis in the Livers of Rats Fed a Choline-deficient, L-Amino Acid-defined Diet¹

Department of Oncological Pathology, Cancer Center, Nara Medical University, Kashihara, Nara 634-8521, Japan [D. N., H. K., A. D., Y. Kob., W. K., T. Ts., Y. Kon.], and Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104 [Y. Kot., K. L. H., H. S., C. A. S., T. Ta., R. A. F.]

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.

¹ This work was supported in part by Grants-in-Aid for Cancer Research (designate 7-1 and 8-2; to Y. Kon.) and for Scientific Research Expenses for Health and Welfare Programs, 2nd-Term Comprehensive 10-year Strategy for Cancer Control, Cancer Prevention, from the Ministry of Health and Welfare of Japan (to Y. Kon.); Grants-in-Aid 06280119 and 09253105 (to D. N.), 09253104 (to A. D.), and 08264108 (to Y. Kon.) for Scientific Research in Priority Areas, Cancer Research, from the Ministry of Education, Science, Sports and Culture of Japan; and NIH Grants GM54878 (to Y. Kot.) and NS35747 (to R. A. F.).

² To whom requests for reprints should be addressed, at the Department of Oncological Pathology, Cancer Center, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan. Phone: 81-744-29-8849; Fax: 81-744-25-7308; E-mail: dnakae@nmugw.cc.naramed-u.ac.jp.

Received 7/20/98. Accepted 8/31/98.

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