ラットにおけるコリン欠乏アミノ酸食による肝発癌に対するphenyl N-terl-butyl nitroneおよびその誘導体のおよぼす影響

Abstract

The present study examined effects of phenyl N-tert-butyl nitrone (PBN) and its derivatives on the early phase of hepatocarcinogenesis in rats fed a choline- deficient, L-amino acid-defined (CDAA) diet. Male Wistar rats, 6 weeks old, were fed the CDAA diet for 16 weeks without or with PBN or its derivatives admixed into the diet at concentrations of 0.009, 0.045 or 0.090%, and then sacrificed. The livers were assessed for the induction of glutathione S-transferase placental form (GST-P)-positive lesions and apoptosis, proliferation and oxidative injuries in hepatocytes. The numbers of GST-P- positive lesions were decreased only by the high dose of PBN. In contrast, the lesion sizes were decreased by all of the doses of 4-OHPBN and the high doses of PBN and 3-OHPBN. PBN, 4-OHPBN and 3-OHPBN inhibited the induction of the borderline cirrhosis, enhan- ced hepatocellular apoptosis in GST-P-positive lesions, inhibited apoptosis in surrounding tissue, and reduced the induction of oxidative damage on nuclear DNA and extranuclear components of hepatocytes. In addition, 4-OHPBN inhibited proliferating activity of hepatocytes both in GST-P-positive lesions and in surrounding tissue. Neither 2-OHPBN nor 2-SPBN exerted any of the effects described above. These results indicate that PBN, 4-OHPBN and 3-OHPBN inhibit the growth of putative preneoplastic lesions induced in the livers of rats fed the CDAA diet by reducing oxidative stress and liver injury. Among these, 4-OHPBN, a major metabolite of PBN, can exert the most superior effects because of the additional inhibition of hepatocyte proliferation. In conclusion, PBN inhibits endogenous hepatocarcinogenesis in rats fed the CDAA diet depending on its metabolic activation into 4-OHPBN, through antioxidative effects and possibly by regulating the oxidative stress-related signal transduction.