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

Abstract

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.

2-Amino-9H-pyrido[2,3-b]indole (AαC) Adducts and Thiol Oxidation of Serum Albumin as Potential Biomarkers of Tobacco Smoke

“…1) (49, 64). Previous studies reported that structurally related aromatic amines, some of which are present in tobacco smoke (1,66), deplete glutathione levels in the liver or ex vivo in hepatocytes of rodents and induce oxidative DNA damage (67)(68)(69); however, the oxidation of albumin was not reported in those studies. In our study, we show that albumin scavenges ROS produced by metabolites of A␣C in human hepatocytes by formation of the oxidized Cys 34 -containing peptides LQQ*C [SO2H] -PFEDHVK, LQQ*C…”

Liver precursor cells increase hepatic fibrosis induced by chronic carbon tetrachloride intoxication in rats

“…This is in line with the proposal that AAF metabolites are able to uncouple mitochondrial respiratory chain and open the permeability pore leading to apoptosis. 42 As a consequence, injured hepatocytes eliminated by apoptosis might provide a sufficient signal to stimulate the LPC compartment while normal hepatocytes cannot proliferate due to AAF toxicity.…”

Suppression of T Lymphocyte Proliferation to Antigenic and Mitogenic Stimuli by Benzo(α)pyrene and 2-Aminofluorene Metabolites

“…Oxidation converts them to N-hydroxy-aminofluorene (N-OH-AF), and Nhydroxy-N-acetylaminofluorene (N-OH-AAF), which covalently bind to DNA. (4) Both BP and AF have tumor initiating and promoting properties. (3) Suppression of immune function is concomitant with a high incidence of cancer in humans and animals, especially in immunocompromised hosts.…”