Acetylaminofluorene metabolism

D. K. Monteith, S. C. Storm, A Comparison of the Inhibition of Deacetylase in Primary Cultures of Rat and Human Hepatocytes Effecting Metabolism and DNA-Binding of 2-Acetylaminofluorene , Cell Biol. Toxicol. 1990, 6, 269-284. 

C. C. Lai, E. C. Miller, A. Liem, The Essential Role of Microsomal Deacetylase Activity in the Metabolic Activation, DNA-(Deoxyguanosin-8-yl)-2-aminofluorene Adduct Formation and Initiation of Liver Tumors by A-Hydroxy-2-acetylaminofluorene in the Livers of Infant Male B6C3Fj Mice , Carcinogenesis 1988, 9, 1295-1302. 

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. 

Clearly, the mechanism(s) underlying the carcinogenesis of acetylaminofluorene is very complex, and sometimes apparently conflicting and confusing data may reflect the fact that several different metabolic pathways are involved, which are more or less predominant in different tissues and in different animal species. It has been suggested, for instance, that the sulfate ester of N-hydroxyacetylaminofluorene is responsible for cytotoxicity and cell death, cell proliferation, and therefore promotion, whereas an N-hydroxyaminofluorene metabolite is responsible for initiation. Thus, both pathways would be necessary (Fig. 7.1). 

Anapolsky A, Teng S, Dixit S, et al. The role of pregnane X receptor in 2-acetylaminofluorene-mediated induction of drug transport and metabolizing enzymes in mice. Drug Metab Dispos 2006 34 405-409. 

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.

Acetylaminofluorene is not carcinogenic 2-acetylaminofluorene is carcinogenic. 2-Acetylami-nofluorene can be metabolized to form N-hydroxy-acetylaminofluorene and 2-aminofluorene, which may covalently bind to the DNA and macromolecules. Ring hydroxylation, however, leads to the formation and excretion of water-soluble conjugates (e.g., glucuronides) of the respective hydroxylated metabolites and detoxification. 

Rudo KM, Dauterman WC, Langenbach R. 1989. Human and rat kidney cell metabolism of 2-acetylaminofluorene and benzo(a)pyrene. Cancer Res 49(5) 1187-1192. 

The A-hydroxylation of acetylaminofluorene and paracetamol are two toxicologically important examples illustrating species differences (see Chapter 7). Another example is the metabolism of amphetamine, which reveals marked species differences in the preferred route, as shown in figure 5,8. Species differences in the rate of metabolism of hexobarbital in vitro correlate with the plasma half-life and duration of action in vivo as shown in table 5,10. This data shows that the marked differences in enzyme activity between species is the major determinant of the biological activity in this case. 

FIGURE 7.1 Some of the possible routes of metabolic activation of acetylaminofluorene (AAF). N-OH-AF N-hydroxyaminofluorene N-OH-AAF N-hydroxyacely/aminqfluorene N-acetoxy AF H-acetoxyaminofluorene N-(dG-8yl)-AF N-deoxyguanosinyl-aminofluorene N-(dG-8yl)-AAF N-deoxyguanosinyl-acetylaminofluorene. P-450 cytochrome(s) P-450 DA deacetylase NAT N-acetyltransferase AHAT N, O-arylhydroxamic acid acyltransferase. 

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