Free radicals in arylamine carcinogenesis.
Free radical processes and their involvement in carcinogenesis is an unresolved question but one subjected to intense investigation recently. Using in vitro systems, we demonstrated that certain heme compounds combined with hydroperoxides catalyzed the oxidation of N-hydroxy-2-fluorenylacetamide (N-OH-2-FAA) to nitroxyl free radical intermediate which dismutated to form 2-nitrosofluorene (2-NF) and N-acetoxy-2-fluorenylacetamide (N-AcO-2-FAA). Ascorbate and certain antioxidants inhibited this reaction. Lipid hydroperoxides were effective substrates for this reaction, especially in target tissue, rat mammary gland parenchymal cells. Cytochrome P420 in the high-spin state catalyzed the reaction effectively but low-spin cytochrome P420 or P450 were ineffective. Recently, we found that 2-NF added covalently to unsaturated carbon-carbon double bonds of membrane lipids to form an adduct termed 2-nitroso-fluorene lipid adduct (N-O-LAF), which, in it oxidized state, exists in the membrane as a nitroxyl free radical. This N-O-LAF undergoes reduction-oxidation changes in the natural membrane. Formation of N-O-LAF occurred in rat liver microsomal membranes by deacylation of N-OH-2-FAA, but the esterase inhibitor paraoxon, prevented its formation from N-OH-2-FAA. The mutagenicity of 2-NF was enhanced in Salmonella typhimurium TA98 if the bacteria were cultured to contain more unsaturated membrane lipids. However, synthesized adducts were only slightly mutagenic.
D000588:Amines; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens; D004578:Electron Spin Resonance Spectroscopy; D005449:Fluorenes / Q000378:metabolism / Q000494:pharmacology; D005609:Free Radicals; D050356:Lipid Metabolism; D008862:Microsomes, Liver / Q000378:metabolism*; D009152:Mutagenicity Tests; D009153:Mutagens; D009603:Nitroso Compounds / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects
D000588:Amines; D002273:Carcinogens; D005449:Fluorenes; D005609:Free Radicals; D009153:Mutagens; D009603:Nitroso Compounds; C012458:2-nitrosofluorene