Graduate Thesis Or Dissertation
 

Mechanisms of action by some inhibitors of aflatoxin B₁ carcinogenesis in rainbow trout

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  • Indole-3-carbinol (I3C) and butylated hydroxyanisole (BHA), anti-carcinogens present in the human diet, were tested for their in vivo and in vitro effect on aflatoxin B₁. (AFB₁) metabolism, and DNA adduct formation in the rainbow trout. Dietary BHA at either 0.3 or 0.03% had no effect on the hepatic tumor incidence of trout exposed to a 0.5 ppm AFB₁ solution as embryos, or when fed prior to and during dietary exposure to 10 ppb AFB₁. Previous studies have shown 0.1% I3C to inhibit AFB₁-induced hepatomas in trout. When fed at 0.2%, I3C produced a 70% reduction in average in vivo hepatic DNA binding of injected AFB₁ over a 21 day period compared to controls. A similar study with 0.3% BHA had no effect on AFB₁-DNA binding over a 7 day period. One hr incubations of AFB₁ with freshly isolated hepatocytes from either BHA-, I3C- or control-fed trout showed no differences in AFB₁ metabolism or DNA binding between BHA hepatocytes and controls. However, I3C hepatocytes had 20% less DNA binding with a 2-fold increase in aflatoxin M₁ production. Additions of 0, 1, 10 or 100 uM BHA or I3C to hepatocytes isolated from trout fed a control diet had no effect on AFB₁-DNA adduct formation except for a 20% decrease in the 100 uM BHA hepatocytes. A 24 hr distribution study of injected [³H]-AFB₁ in trout fed 0.3% I3C showed less total radioactiuity in the blood and liver at all times examined, compared to controls. These reductions were accountable primarily as reduced levels of AFB₁ bound to red blood cell DNA, reduced plasma levels of the metabolite aflatoxicol (AFL), and decreased levels of AFB₁ and polar metabolites in the liver of I3C trout. Total radioactivity was significantly elevated in the bile of I3C fish resulting from a 7-fold increase in aflatoxicol-n. glucuronide levels over controls. AFL glucuronide levels were similar between treatments. Total radioactivity remaining in the carcasses of I3C or control trout was similar. These data indicate that I3C inhibits AFB₁ hepatocarcinogenesis in trout through changes in carcinogen distribution, metabolism and elimination leading to reduced initial DNA damage. BHA does not appear to alter enzymes responsible for AFB₁ metabolism, and though it may have a weak direct affect on AFB₁-DNA adduct formation, this does not appear to be of importance in vivo since BHA had no effect on AFB₁-induced carcinogenesis.
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