2-acetylaminofluorene carcinogenicity

A well documented species difference in susceptibility to acetylaminofluorene carcinogenicity is the resistance of the guinea-pig. This affords an interesting illustration of the... 

The glucuronidation of bifirubin is discussed in Chapter 32 the reactions whereby xenobiotics are glu-curonidated are essentially similar. UDP-glucuronic acid is the glucuronyl donor, and a variety of glu-curonosyltransferases, present in both the endoplasmic reticulum and cytosol, are the catalysts. Molecules such as 2-acetylaminofluorene (a carcinogen), aniline, benzoic acid, meprobamate (a tranquilizer), phenol, and... 

Amides that undergo N-hydroxylation are often amides of arylamines (Fig. 4.87) some of which are carcinogens such as 2-acetylaminofluorene (Fig. 4.87). Initial N-hydroxylation of a hydrazine is similar to that of an amine however, further oxidation can lead to the formation of nitrogen gas and reactive species. The two-electron oxidation pathway is shown in Figure 4.87. Hydrazines also undergo one-electron oxidations but the intermediates are short-lived and these pathways are less well defined (154). 

Lai CC, Miller JA, Miller EC, et al. N-sulfooxy-2-aminofluorene is the major ultimate electrophilic and carcinogenic metabolite of N-hydroxy-2-acetylaminofluorene in the livers of infant male C57BL/6J x C3H/HeJ FI (B6C3F1) mice. Carcinogenesis 1985 6(7) 1037— 1045. 

Toxicology. 2-Acetylaminofluorene (AAF) is a potent carcinogen in dogs, hamsters, and rats. 

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. 

An important example toxicologically is the N-hydroxylation of 2-acetylaminofluorene (Fig. 4.22). N-hydroxylation is one of the reactions responsible for converting the compound into a potent carcinogen. A second example is the N-hydroxylation of isopropylhydrazine, thought to be involved in the production of a hepatotoxic intermediate (chap. 7, Fig. 7.25). 

Work with the carcinogen acetylaminofluorene found that residues of the compound in ribosomal RNA may correlate more closely with liver tumor formation than residues in DNA. Direct interactions with the mechanisms of protein synthesis, or with DNA and RNA polymerase enzymes, can also be seen as possible mechanisms. For instance, a modification of the polymerase enzymes by a carcinogen, either directly or indirectly, could lead to the erroneous replication of DNA or RNA and hence the permanent incorporation of a mutation. 

The reactive nitrenium or carbonium ions postulated to be produced will react with nucleophilic groups in nucleic acids, proteins, and sulfydryl compounds such as glutathione (GSH) and methionine. The arylation of DNA by acetylaminofluorene has been demonstrated in vivo and in vitro. The involvement of sulfate conjugation brings other factors into play. Depletion of body sulfate reduces, and supplementation with organic sulfate increases the carcinogenicity of acetylaminofluorene. The production of covalent adducts between acetylaminofluorene and cellular macromolecules in vivo can be shown to be correspondingly decreased and increased by manipulation of body sulfate levels. 

Glucuronidation of the resulting hydroxyl derivatives is also induced by phenobarbital pretreatment. Consequently, pretreatment of animals with both these agents reduces the carcinogenicity of acetylaminofluorene. This illustrates the difficulty of predicting the effect of environmental influences on toxicity when multiple metabolic pathways are involved. 

N-Oxidation. (V-oxidation can occur in a number of ways, including hydroxylamine formation, oxime formation, and N-oxide formation, although the latter is primarily dependent on the FMO enzyme. Hydroxylamine formation occurs with a number of amines such as aniline and many of its substituted derivatives. In the case of 2-acetylaminofluorene the product is a potent carcinogen, and thus the reaction is an activation reaction (Figure 7.6). 

Fiber was shown to inhibit carcinogenicity of 2-acetylaminofluorene more than thirty years ago (7,17). A recent review (18) has pointed out the lack of consistency in studies of fiber effects on experimental colon carcinogenesis. Investigators use different strains of rat, stock or semipurified diets, and different carcinogens administered orally, subcutaneously or intrarec-tally (Table v). Ward et al. (19) found cellulose to have no effect on the carcinogenicity of azoxymethane (AOM) in male Fisher rats fed a semipurified diet. Freeman et al. (20), on the other hand, found cellulose to protect male Wistar rats from colon cancer induced by subcutaneous injection of 1,2-dimethylhydrazine (DMH). 

Banner et al., (21) found that selenium did not influence the acute alterations induced by 2-acetylaminofluorene or methylazoxymethanol and suggested that the anticarcinogenic properties of selenium were due to a mechanism other than an interference with carcinogen activation and interaction with cellular macromolecules. 

Figure 22.15. Metabolism of A-2-acety 1-2-ami noII uorene (AAF) to form the ultimate carcinogens that damage DNA. Two metabolites are reactive toward DNA, forming AF-dG and AAF-dG as the major DNA adducts, respectively. AAAF, A-acetoxy-A-2-acetylaminofluorene.

Specific temperatures for the incineration of all known or suspected chemical carcinogens have not been determined. Work conducted at the National Center for Toxicological Research Laboratories (NCTRL), Food and Drug Administration, Jefferson, Arkansas 72079 has shown that 2-Acetylaminofluorene may be... 

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