New insights into carcinogenesis of the classical model arylamine 2-acetylaminofluorene.
2-Acetylaminofluorene (AAF) is a complete carcinogen in rat liver. The genotoxic effects of reactive metabolites are considered necessary but not sufficient to explain tumor formation. An overview is given of an AAF-feeding experiment designed to demonstrate early effects, preceding the development of enzyme-altered foci to support the hypothesis that toxic effects lead to a cirrhosis-like transformation as a prerequisite for the expansion of initiated foci and how those effects influence the dose-time-response relationship of tumor formation. Male Wistar rats were fed 0.005, 0.01, 0.02, 0.04 and 0.08% AAF in the diet for 2, 4, 8, and 16 weeks. GST-P-positive foci developed more than proportionately only at 16 weeks. As a first sign of morphological alterations the number of apoptoses increased (2 weeks), the proliferation rate followed with some delay and was maximal at 4 weeks. The most sensitive parameter for adaptive responses was the inhibition of the mitochondrial permeability transition, studied ex vivo. All parameters increased dose-dependently at low doses. A threshold could not be detected, but effects developed much more gradually with the lowest, non-toxic dose. The situation of massive development of foci observed with the higher doses at 16 weeks was not reached. Apoptosis and proliferation rate reach a plateau between 4 and 8 weeks with some of the doses indicating a period in which some balance between adaptation and stress response exists.
Bitsch
A
A
Department of Toxicology, University of Würzburg, Germany.
Klöhn
P C
PC
Hadjiolov
N
N
Bergmann
O
O
Neumann
H G
HG
D015073:2-Acetylaminofluorene / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis; D002273:Carcinogens / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008930:Mitochondria, Liver / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
D002273:Carcinogens; D015073:2-Acetylaminofluorene