Chemoprevention of aflatoxin B1-induced carcinogenesis by indole-3-carbinol in rat liver--predicting the outcome using early biomarkers.
Indole-3-carbinol (I3C) was examined for its ability to inhibit aflatoxin B1 (AFB1)-induced hepatocarcinogenesis in male Fischer rats when administered either before or after the carcinogen. After 13 weeks, animals pretreated with I3C (0.5% in the diet) for 2 weeks prior to administration of AFB1 and with continuing treatment during exposure to the carcinogen were protected from development of preneoplastic lesions, as determined by the classical markers gamma-glutamyltranspeptidase (GGT) and glutathione S-transferase (GST) P. In animals receiving AFB1 for 6 weeks before treatment with I3C, there was no obvious protective effect at 13 weeks compared with animals receiving only AFB1. Using cytokeratin 18 expression as a marker, animals fed AFB1 alone had a small number of positive foci at 13 weeks. However, no cytokeratin-positive foci were visible in the majority of livers from either group receiving I3C in combination with AFB1 and after 43 weeks all animals in these groups were protected from liver tumour formation. These results suggest that expression of cytokeratin 18, a later phenotypic change in foci than induction of GST-P and GGT, correlates more closely with tumour outcome in this model. I3C appeared to retard progression of AFB1-induced carcinogenesis at both the initiation and promotion stages. Continuous treatment with I3C for 13 weeks caused significant induction of CYP1A1, 1A2, 3A and 2B1/2, GST Yc2, aflatoxin B1 aldehyde reductase and quinone reductase. Such alteration of the drug metabolizing capacity of the liver by I3C contributes to blocking of initiation, while the observed inhibition of ornithine decarboxylase, a rate limiting enzyme in polyamine biosynthesis, and of tyrosine kinase activity may contribute to the suppressive effect of I3C.
Manson
M M
MM
MRC Toxicology Unit, University of Leicester, UK. mmm2@le.ac.uk
Hudson
E A
EA
Ball
H W
HW
Barrett
M C
MC
Clark
H L
HL
Judah
D J
DJ
Verschoyle
R D
RD
Neal
G E
GE
D016604:Aflatoxin B1 / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000449:Aldehyde Reductase / Q000378:metabolism; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor; D002273:Carcinogens / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D007633:Keratins / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D011230:Precancerous Conditions / Q000139:chemically induced / Q000517:prevention & control; D051381:Rats; D011916:Rats, Inbred F344; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D016588:Anticarcinogenic Agents; D014408:Biomarkers, Tumor; D002273:Carcinogens; D007211:Indoles; D007633:Keratins; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; C016517:indole-3-carbinol; C082765:aflatoxin B1 aldehyde reductase; D000449:Aldehyde Reductase; D005723:gamma-Glutamyltransferase; D005982:Glutathione Transferase