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.