Hopp M L, Matsumoto M, Wendell B, Lee C, Oyasu R
Cancer Res. 1976 Jan;36(1):234-9.
Indole is known to suppress the hepatotoxicity and carcinogenicity of 2-acetylaminofluorene (AAF) in rats and hamsters. For elucidation of the mechanism of its protective role, 2 experiments were conducted using young male rats. In the 1st experiment, the 24-hr biliary excretion of N-hydroxy-2-acetylaminofluorene (N-OH-AAF)-glucuronide was measured after 2 and 4 weeks of dietary administration of 0.03% AAF with or without 1.6% indole. The amount of [9-14C]N-OH-AAF that was excreted as the glucuronide following a single i.p. injection of [9-14C]AAF was lower after 2 weeks in animals fed AAF and indole, as compared to those fed AAF alone [1.5 +/- 1.2% versus 19.6 +/- 3.6% S.E. (p less than 0.001)]. After 4 weeks of AAF administration without indole, the biliary excretion fell to 4.8 +/- 2.1%. This was also significantly higher than that of the animals fed both AAF and indole [1.8 +/- 1.2% (p less than 0.025)]. The suppressive role of indole on the conjugate excretion was also reflected in a decreased biliary excretion of all [9-14C]AAF metabolites in animals treated with indole alone. In the 2nd experiment, the protective action of indole was assessed by survival following daily i.p. injections of N-OH-AAF and Na2SO4 solution. Na2SO4 increased the hepatotoxicity of N-OH-AAF. Indole suppressed the toxicity of N-OH-AAF even in the presence of Na2SO4. This protective role of indole was partially overcome only when excess sulfate was coadministered. These results indicate that indole suppresses the biliary excretion of the O-glucuronide of N-OHAAF during the initial exposure of the animal to the carcinogen, possibly reflecting decreased N-OH-AAF formation. Indole also modifies the metabolism of AAF FOLLOWING N-hydroxylation, perhaps activating N-OH-AAF, depending upon the concentration of sulfate available.
已知吲哚可抑制2-乙酰氨基芴（AAF）对大鼠和仓鼠的肝毒性及致癌性。为阐明其保护作用机制，使用雄性幼鼠进行了2项实验。在第一项实验中，给幼鼠喂食含0.03% AAF且添加或不添加1.6%吲哚的饲料，2周和4周后测量N-羟基-2-乙酰氨基芴（N-OH-AAF）-葡萄糖醛酸苷的24小时胆汁排泄量。单次腹腔注射[9-14C]AAF后，以葡萄糖醛酸苷形式排泄的[9-14C]N-OH-AAF量，在喂食AAF和吲哚的动物中，2周后低于仅喂食AAF的动物[1.5±1.2%对19.6±3.6%标准误（p＜0.001）]。在无吲哚的情况下给予AAF 4周后，胆汁排泄量降至4.8±2.1%。这也显著高于同时喂食AAF和吲哚的动物[1.8±1.2%（p＜0.025）]。吲哚对结合物排泄的抑制作用还体现在单独用吲哚处理的动物中，所有[9-14C]AAF代谢物的胆汁排泄量均减少。在第二项实验中，通过每日腹腔注射N-OH-AAF和硫酸钠溶液后的存活率评估吲哚的保护作用。硫酸钠会增加N-OH-AAF的肝毒性。即使存在硫酸钠，吲哚仍能抑制N-OH-AAF的毒性。仅在同时给予过量硫酸盐时，吲哚的这种保护作用才会部分被克服。这些结果表明，在动物初次接触致癌物期间，吲哚可抑制N-OH-AAF的O-葡萄糖醛酸苷的胆汁排泄，这可能反映了N-OH-AAF生成减少。吲哚还会在N-羟基化后改变AAF的代谢，可能会根据可用硫酸盐的浓度激活N-OH-AAF。
