Effects of the anticarcinogen indole-3-carbinol on Xenobiotic metabolizing enzymes in rainbow trout Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/1831cn06h

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  • Indole-3-carbinol (I3C) inhibits chemically induced tumor formation in rodents and rainbow trout. This study examines the effect of I3C and its analog, indole-3-acetonitrile (I3N) on xenobiotic-metabolizing enzyme systems. The modulation of these enzyme systems have been shown to have significant effects on the interaction of chemical carcinogens and cellular constituents. Rainbow trout were fed 500, 1000 and 2000 ppm dietary levels of I3C and 50, 500 and 1000 ppm dietary levels of I3N for 8 days. β-napthoflavone (BNF), which is also an effective anticarcinogen in the trout, was fed at a 500 ppm dietary level and was used as a positive LM4b (a cytochrome P-450 isozyme) inducing control. Enzyme activities assayed were: ethoxyresorufin-O-deethylase (EROD), ethoxycoumarin-O-deethylase (ECOD), glutathione S-transferase (GST), and uridine diphosphoglucuronosyl transferase (UDPGT). Total cytochrome P-450 content was determined spectrophotometrically by the CO reduced method. The specific P-450 isozymes, LM2 and LM4b, were detected quantitatively using the western blot method. The BNF diet induced EROD and ECOD activities by an average of 17 fold and 5.5 fold, respectively. Total P-450 content was increased 2-fold; the P-450 isozyme LM4b was induced more than 5-fold, but LM2 content remained unchanged. This diet increased UDPGT activity 1.5-2-fold, but GST activity was not induced by dietary BNF. Neither I3C nor I3N induced the activity levels of the enzymes assayed at any administered dietary levels, which have previously shown to inhibit tumor formation and reduce formation of carcinogen-DNA adducts. Thus, the anticarcinogenic mechanism of I3C may proceed in trout by mechanisms other than enzyme induction. Further experiments on the effect of I3C and I3C acid condensation products (RXN) on in vitro AFB1-DNA binding resulted in a 40% and 48% inhibition of AFB1-DNA binding by I3C and RXN, respectively. Additions of RXN at levels much lower than those estimated to exist in vivo in hepatic tissue resulted in a significant reduction in AFB1-DNA formation suggesting that even small levels of RXN offers protection against the genotoxic effect of AFB1. However, in vitro additions of neither I3C nor RXN had an effect on DNA binding using AFBI-CI₂, an aflatoxin analog that does not require enzymatic activation. These results suggest that the primary mechanism for I3C inhibition of AFB1 induced carcinogenesis may proceed by inhibiton of formation of the ultimate electrophile, i.e. by reversible inhibition of cytochrome P-450.
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