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. 2005 Aug 19;94(1):26–31. doi: 10.1111/j.1349-7006.2003.tb01347.x

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

Dai Nakae 1,✉, Hideki Kishida 2,3, Tomonori Enami 4,5, Yoichi Konishi 2,4, Kenneth L Hensley 2, Robert A Floyd 2,6, Yashige Kotake 2
PMCID: PMC11160203  PMID: 12708470

Abstract

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 cholinedeficient, 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. (Cancer Sci 2003; 94: 26–31)

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