Proximate carcinogens

In response to injury caused by various pollutants, toxicants, and carcinogens, proximal and distal airway epithelial cells lose their normal secretory functions and express squamous and keratinis-ing properties (Plopper 1997). 

The key to hexavalent chromium s mutagenicity and possible carcinogenicity is the abiHty of this oxidation state to penetrate the cell membrane. The Cr(VI) Species promotes DNA strand breaks and initiates DNA—DNA and DNA-protein cross-links both in cell cultures and in vivo (105,112,128—130). The mechanism of this genotoxic interaction may be the intercellular reduction of Cr(VI) in close proximity to the nuclear membrane. When in vitro reductions of hexavalent chromium are performed by glutathione, the formation of Cr(V) and glutathione thiyl radicals are observed, and these are beHeved to be responsible for the formation of the DNA cross-links (112). 

The experiments with deuterium-labeled nitrosamines illustrate two important points. One is that oxidation of nitrosamines takes place at more than one position in the molecule, and the outcome of the balance of such competing reactions probably is the determinant of carcinogenic potency. The second is that the reason for the failure of carcinogenesis to be mirrored in many cases by the microsomally activated bacterial mutagenicity is that there can be several metabolic steps leading to formation of the proximate carcinogenic agent and not all of these need necessarily involve microsomal enzymes. ... 

N-nitroso compounds, once formed and present in vivo> generally do not revert easily or readily back to precursors. Instead, in vivo> they are metabolized or otherwise converted to alkylating agents as terminal or proximal carcinogens. 

Cerniglia CE, RH Dodge, DT Gibson (1982d) Fungal oxidation of 3-methylcholanthrene formation of proximate carcinogenic metabolites of 3-methylcholanthrene. Chem-Biol Interactions 38 161-173. 

Methylcholanthrene (3-MC) is a potent carcinogen, intermediate in activity between DMBA and BP (27,77). It was first prepared in 1925 by Wieland from desoxycholic acid (89). Biological studies have tentatively identified the 9,10-dihydrodiol (24a) and/or its 1- or 2-hydroxy derivatives (24b and 24c) and the corresponding diol and triol epoxides (25 -c) as the proximate and ultimate carcinogenic forms, respectively, of 3-MC (90-93). 

Two specific suggestions concerning the role that the reversible physical binding of proximate and ultimate carcinogens derived from BP play in carcinogenesis have been made. The first is based on recognition that DNA-BPDE complex formation precedes re-... 

Although several N-methyl-substituted arylamines have been shown to be carcinogenic (184-186), metabolic activation pathways have been investigated primarily for the hepatocarcinogenic aminoazo dyes, N-methyl-4-aminoazobenzene (MAB) and its 3 -methyl derivative (9,21, 22,187,188). N-Hydroxy-N-methyl arylamines are generally regarded as proximate carcinogenic metabolites (22,187,189) and have been shown to be converted to electrophilic N-sulfonyloxy derivatives by hepatic sulfotransferases (9,187) or to reactive N-arylnitrones by air oxidation (21). 

The conformations of the 1- and 3-nitro-BaP metabolites were determined through analysis of their NMR spectra (145-146). Both 1- and 3-nitro-BaP-trans-7,8-dihydrodiols existed predominantly in quasi-diequatorial conformations, which corresponds to the preferred conformation of the proximate carcinogen BaP-trans-7,8-dihy-drodiol (149). This suggests that these dihydrodiol metabolites may be converted into electrophilic diol epoxides and in support of this contention, the stereochemistries of 1- and 3-nitro-BaP-... 

It is of more than a little interest to note that the sites of tumor formation do not always match across species. Benzidine, a substance once widely used in dye manufacture, was shown many years ago to be a carcinogenic risk for the bladder in workers exposed to excessive levels. The rat bladder is not responsive to this substance, but its liver is. It wasn t until Wilhelm Hueper turned to the dog that bladder cancer could be reproduced in a laboratory animal. It is now understood that benzidine metabolism is similar in dogs and people, and that metabolism in the rat takes a different course. It is also understood that certain benzidine metabolites, and not benzidine itself, are the proximate causes of tumors. Knowledge of metabolic differences helps explain the species similarities and differences in tumor response. If we had available the rat data and no human data, we would be in error to conclude that benzidine was a cause of human liver cancer. 

Animal studies have indicated that N-hydroxy-2-acetylaminofluorene (M-hydroxy-AAF) is a proximate carcinogenic metabolite of AAF AAF is not carcinogenic in the guinea pig, and no M-hydroxylation of AAF has been detected in vivo or in vitro in this species however, administration of N-hydroxy-AAF causes tumors in guinea pigs. In addition, N-hydroxy-AAF has proved to be a carcinogen of much greater potency than AAF in rats, mice. 

Thus, it is apparent that the initial a-hydroxylation of nitrosamine constitutes a possibly important pathway to produce the so-called proximate carcinogen. The a-hydroxylated nitrosamines have eluded direct isolation, although derivatives such as esters and ethers have been prepared by various groups (4, 5, 6, 7, 8). These materials, particularly g-acetoxydimethylnitrosamine (9), have been shown to be very potent carcinogens. 

Miller, E.C. and Miller, J.A. (1966) Mechanisms of chemical carcinogenesis -nature of proximate carcinogens and interactions with macromolecules. Pharmacol. Rev., 18 (1), 805-838. 

Cell damage induced by chemical carcinogens involves the conversion in the body of a proximate carcinogen (inert) to the ultimate carcinogen that is a reactive electrophilic compound. This ultimate carcinogen may then interact or, more frequently, combine covalently with intracellular components, such as DNA, RNA, phospholipids, or glutathione. 

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