Role of tissue exposure and DNA lesions for organ-specific effects of carcinogenic trans-4-acetylaminostilbene in rats.

Abstract

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.

Use of monoclonal and polyclonal antibodies against DNA adducts for the detection of DNA lesions in isolated DNA and in single cells.

“…Such experiments may reveal which of the various adducts is responsible for the induction of the genetic effects observed (i.e., the key lesion). Although total adduct formation in DNA in some cases could not be correlated with tumor formation (17), it may well be that a specific type of lesion among the various adducts that are induced is directly related to the development of neoplasia or the occurrence of heritable disorder (52). Total adduct formation, e.g., measured in various organs after treatment of an animal with radiolabeled genotoxicants, does not necessarily reflect the relative abundance of these key lesions, because various types of damage may follow different, organspecific kinetics of formation and repair.…”

“…In several cases, the extent of formation of DNA adducts has been correlated in animal experiments with the carcinogenic potency of the compounds studied (15,16). In other instances, no such correlation could be found (17). The assumption was made that, in these cases, secondary factors such as tumor promotion and/ or progression ultimately determine whether a tumor will develop or not.…”

Use of Monoclonal and Polyclonal Antibodies against DNA Adducts for the Detection of DNA Lesions in Isolated DNA and in Single Cells

“…Mutations in somatic cells are thought to represent an early stage in carcinogenesis (12,13), whereas mutations in germ cells may give rise to heritable diseases, among which there are some tumors of a hereditary nature (14). In other instances, no such correlation could be found (17). In other instances, no such correlation could be found (17).…”

The life of Hans-Günter Neumann and his contributions to chemical carcinogenesis

“…Indeed, trans-4-acetyl-aminostilbene (trans-AAS), a metabolite of trans-DAS ( Fig. 1) and not a liver or kidney carcinogen per se, gave rise to hepatic tumors in rats when liver cell proliferation was stimulated by partial hepatectomy or certain liver tumor promotors such as phenobarbital, the insecticide DDT or the synthetic estrogen diethyl-stilbestrol (Neumann 1983). This approach already considered the multistage concept of carcinogenesis (Scott et al 1984) suggesting that initiation is the process of introducing irreversible lesions in genomic DNA, whereas the promotion regimen enables proliferation and accumulation of preneoplastic cells.…”