Suppressive Role of Indole on 2-Acetylaminofluorene Hepatotoxicity1

served in all 26 animals treated with AAF alone, while only 7 of 27 animals treated with AAF and indole developed this lesion (13). In addition, none of the AAFand the indole treated animals developed cholangiocarcinoma, as did 4 of the AAF-treated animals. It has been shown that AAF requires biochemical activa tion in the liver, in the form of hydroxybation of the nitrogen yielding N-OH-AAF (2, 11). This derivative is more carcino genic than the parent compound in sensitive species, and is active at the site of the injection (5, 12, 18). It is also active in species in which the parent compound is inactive (9). The ability of liver to N-hydnoxylate AAF can be assessed in vitro (1, 8) and in vivo (8) by measuring the production of the 0glucuronide of N-OH-AAF, the major metabobite of N-OH AAF in the rat liver (6). Irving et a!. (6) have shown that rats, a species susceptible to hepatotoxicity and carcinogenicity by AAF, excrete a high percentage of a test dose as N-OGI AAF on bile. In rabbits, a species resistant to AAF, the biliany excretion of N-OGI-AAF was much less. Subsequent studies strongly indicate that N-OH-AAF must undergo further activation in order to manifest its hepatocar cinogenicity. At least one of these ultimate carcinogenic forms leading to liver cancer in rats has been shown to be the sulfate ester of N-OH-AAF (3, 17). This view was sup ported by increased hepatotoxicity and carcinogenicity of N-OH-AAF in the presence of acetanilide and excess dietary sulfate (4, 17). It was shown that susceptible species exhibit higher sulfotransfenase activity than nonsusceptible species (3, 7). Indole has been shown to decrease [9-'4C]N-OH-AAF binding to DNA, while increasing the binding to microsomal protein(9). Our present studies were undertaken to investigate the protective role of indole and its relation to alterations of the metabolism of AAF in vivo. In the 1st experiment, the biliary excretion of conjugated N-OH-AAF was measured following a short period of dietary carcinogen treatment with on with out indabe. In the 2nd experiment, the effect of indole on NOH-AAF toxicity was assessed.