Aromatic Amines in Experimental Cancer Research: Tissue-Specific Effects, an Old Problem and New Solutions

• Published in: Critical reviews in toxicology 2007-03, Vol.37 (3), p.211-236
• Main Author: Neumann, H.-G.
• Format: Article
• Language: English
• Subjects: Amines - toxicity; Animals; Apoptose; Apoptosis - drug effects; Aromatic Amines; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens - toxicity; Cell Proliferation - drug effects; Chemical agents; Chemical and industrial products toxicology. Toxic occupational diseases; Dose-Response Relationship, Drug; Humans; Liver Neoplasms - chemically induced; Liver Neoplasms - pathology; Liver Tumors; Medical sciences; Mitochondria; Mitochondria - drug effects; Mitochondria - physiology; Neoplasms, Experimental - chemically induced; Neoplasms, Experimental - pathology; Organ Specificity; Oxygen - physiology; Rats; Tissue Specificity; Toxicology; Tumors; Various organic compounds
• ISSN: 1040-8444; 1547-6898
• DOI: 10.1080/10408440601028603

Carcinogenic aromatic amines usually produce tumors in specific target tissue, such as 2-acetylaminofluorene (AAF) producing liver tumors in rats, in contrast to some other structurally related arylamines. A hypothesis is presented that explains the mode of action in this rat liver model. Genotoxic and nongenotoxic effects work together and make AAF a complete rat liver carcinogen. The cytotoxic, promoting effects are particularly important. N-Hydroxy-2-aminofluorene and 2-nitrosofluorene, two metabolites of AAF, are able to uncouple the mitochondrial respiratory chain. They entertain a redox cycle that removes electrons from the respiratory chain and impairs ATP production. The dose-dependent opening of the mitochondrial permeability transition pore signals the viability of the cell. If the pore is opened to a certain extent, the cell is eliminated by apoptosis. As a consequence, oval cells proliferate, and as this process is overloaded, the liver transforms into a cirrhosis-like situation and thus provides the conditions under which initiated liver cells develop tumors. Such an interpretation is based on assumptions that have been debated for a long time. Some of these often forgotten developments are reviewed in support of the hypothesis, which allows a more comprehensive view of the complex in vivo situation at a time when in vitro models prevail.