Redox cycle of stable mixed nitroxides formed from carcinogenic aromatic amines

Abstract

1. Of the carcinogenic aromatic nitrogenous compounds investigated, 10 out of 11 were found to be biotransformed in rabbit liver microsomal preparations to nitroxide radicals, as detected by ESR spectroscopy; with non-carcinogenic nitrogenous compounds only 2 out of 8 formed nitroxide radicals. 2. The radicals are stable mixed nitroxides formed by covalent binding of the aromatic nitroxide to endogenous constituents of the microsomal membrane with preservation of the nitroxide radical group (spin-trapping). 3. From the high chemical stability and the observed ESR spectra, spin-label-like structures can be deduced. 4. From this and the known one-electron redox properties of spin-labels, a redox cycle catalysing the production of reactive oxygen species and involved in tumour initiation and/or promotion by aromatic nitrogenous compounds is proposed.

Role of oxygen radicals in tumor promotion

“…Biomimetic SOD also inhibits both the initiating [Solanki et al, 19841 and complete carcinogenic action [Egner PA and Kensler TW, unpublished observations) of 7,12-dimethylbenz[a]anthracene in mouse skm. Other carcinogens with diverse target specificities, such as benzene, anthracyclines, diethylstilbestrol, bleomycin, and aromatic amines, can also produce oxy radicals that may be important to their respective "promoter" activities [Greenlee et al, 198 1;Doroshow, 1983;Metzler, 1981;Borek and Troll, 1983;Nakayama et al, 1983;Stier et al, 1980; Kensler and Trush, 19841. …”

2‐Nitrosofluorene and N‐hydroxy‐2‐aminofluorene react with the ubiquinone‐reduction center (center N) of the mitochondrial cytochrome bc1 complex

“…We then determined whether this reaction forms an un-Dit Dit stable nitroxyl radical by one-electron reduction of NOF that is expected to autoxidize readily [1,13] and could explain succinate-dependent 02 consumption in mitochondria (cf. Fig.…”

Pathobiologic and Metabolic Aspects of Mammary Gland Tumorigenesis by N-Substituted Aryl Compounds

“…In theory, electrophilic species in the rat mammary gland may be generated from N-hydroxy-2-FAA via an intramolecular N-O-acetyltransfer catalyzed by N-O-acyltransferase, one-electron oxidation to the nitroxyl radical catalyzed by a peroxidase/peroxide system, 179 or conjugation to N-O-glucuronide catalyzed by UDP-glucuronyltransferase (31). Activation of N-hydroxy-2-FAA via all three mechanisms occurs to a significant extent in the livers of species susceptible and nonsusceptible to hepatocarcinogenesis (32)(33)(34). Therefore, carcinogenicity does not appear to be determined solely by these activation mechanisms.…”

“…Oxidation of carcinogenic aromatic amines to nitroxide free radicals by hepatic microsomal enzymes, presumably the cytochrome P450 system, has been reported (33,38). Since mammary microsomes contain a considerably less powerful mixedfunction oxidase than hepatic microsomes (16), we looked for other cytochrome systems that might participate in this oxidation.…”

“…Additions of aryl-nitroso compounds to double bonds of lipids (42) or spin-trapping of nitroxyl free radicals of hydroxylamines by membrane components (33) may cause membrane perturbations or structural membrane changes thereby affecting transport. Conceivably, transport of DNAreactive carcinogens could be facilitated through carcinogen-primed membranes.…”