4-acetylaminostilbene and Liver-Neoplasms

2-Acetylaminofluorene (AAF) is one of the most widely studied model carcinogens. It produces liver tumors in rats. Comparison with other arylamides shows that promutagenic DNA lesions are necessary but not sufficient to explain this tissue-specific effect. Mutagenicity of AAF was studied in AS52 cells and compared with that of 2-acetylaminophenanthrene and trans-4-acetylaminostilbene which are incomplete carcinogens in rat liver. The major mutations were G to T transversions in all cases. All three acetamides acted as initiators in an initiation-promotion experiment with phenobarbital as a promoter. Chronic toxic effects of AAF were attributed to specific effects of AAF metabolites on mitochondrial respiration. Electron drainage by 2-nitrosofluorene causes an uncoupling effect on oxidative phosphorylation in vitro. Corresponding compensatory effects were observed in vivo. Initiating as well as promoting properties of AAF are therefore considered responsible for the generation of rat liver tumors. The results support the hypothesis that genotoxic effects generate initiated cells which begin to proliferate only when microcirculation is disturbed due to cirrhotic alterations. These are triggered by non-genotoxic interference with mitochondrial respiration and oxidative phosphorylation.

Topics: 2-Acetylaminofluorene; Animals; Cell Survival; Liver Neoplasms; Mitochondria, Liver; Mutagens; NAD; Oxidation-Reduction; Phenanthrenes; Rats; Rats, Wistar; Stilbenes

The synergism of two carcinogenic aromatic amines with different tissue specificities was studied at the level of initiation in Wistar rats. Gamma-glutamyl transpeptidase and glutathione S-transferase P were used as markers for preneoplastic foci in liver. 2-Acetylaminofluorene (AAF) is a complete rat liver carcinogen, whereas trans-4-acetylaminostilbene (AAS) produces ear duct tumors quite selectively, but also acts as a strong initiator in rat liver. When these carcinogens were administered sequentially as two doses of each or simultaneously as four doses of a mixture to neonate animals, which then were treated with phenobarbital in the drinking water for promotion, the initiating activity was additive. When these chemicals were given to young adult animals within 4 weeks in two series of four doses, followed by partial hepatectomy and phenobarbital in the drinking water, the number of preneoplastic foci was greater in groups which had received AAS in both series or in the second series after AAF than in those groups which had received only AAF or AAF in the second series. The average size of foci depended clearly on the sequence in which the two carcinogens were administered. The foci were larger when AAF was given after AAS. The results support the notion that AAS is a strong initiator in rat liver, and that AAF, which is a complete liver carcinogen, has promoting properties under certain circumstances in addition to its initiating properties. The two carcinogens seem to produce the initiating lesions independently but the extent of initiation is additive in this model situation. The simplified neonatal rat liver model appears to be particularly suitable for investigating initiating properties and is proposed for studies of synergistic effects of genotoxic chemicals on the initiation stage, independent of organotropism. It avoids a number of complicating factors related to treatment schedule, forced proliferation rate and toxicity in other models.

Topics: 2-Acetylaminofluorene; Aging; Animals; Biomarkers, Tumor; Carcinogens; Drug Synergism; Female; gamma-Glutamyltransferase; Glutathione Transferase; Hepatectomy; Liver; Liver Neoplasms; Male; Phenobarbital; Precancerous Conditions; Rats; Rats, Wistar; Sex Factors; Stilbenes; Time Factors

trans-4-Acetylaminostilbene is acutely toxic to the glandular stomach and produces sebaceous gland tumors in rats quite specifically. Metabolism, tissue exposure to reactive metabolites, DNA binding and persistence of DNA lesions are implicated in tissue susceptibility, but nothing indicates that one of these parameters determines the biological effect. All tissues are exposed to reactive metabolites, liver as a nontarget tissue ranking highest. DNA binding in this tissue, however, is not irrelevant to tumor formation, but rather indicates the presence of initiating lesions. They can be amplified by partial hepatectomy and/or promoters, such as phenobarbital, DDT and diethylstilbestrol. Liver tumors are formed in high yields with these treatments, and mammary tumors also occur. trans-4-Acetylaminostilbene is therefore considered to be an incomplete carcinogen in these tissues and may initiate cells in other tissues as well. Apparently it lacks promoting properties which are supposed to be unrelated to reactive metabolites. It is concluded that DNA lesions do not reflect tissue risk, but rather secondary effects ultimately determine where the process of tumor formation starts and how fast it develops.

Topics: Animals; Binding Sites; Carcinogens; DNA; DNA Repair; Hepatectomy; Liver Neoplasms; Neoplasms, Experimental; Rats; Stilbenes