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. / Graduation date: 1989
| Identifer | oai:union.ndltd.org:ORGSU/oai:ir.library.oregonstate.edu:1957/27196 |
| Date | 03 June 1988 |
| Creators | Swanson, Hollie I. |
| Contributors | Bailey, George S. |
| Source Sets | Oregon State University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
Page generated in 0.0025 seconds