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Acetylaminofluorene metabolic activation

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. [Pg.175]

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. [Pg.498]

Fig. 1. Potential pathways for the metabolic activation of 2-aminofluorene (1) or 2-acetylaminofluorene (2) as determined by in vitro metabolism studies. Fig. 1. Potential pathways for the metabolic activation of 2-aminofluorene (1) or 2-acetylaminofluorene (2) as determined by in vitro metabolism studies.
Interestingly, the amount of S9 or microsomes needed for the metabolic activation affects the response of the two compounds in opposite fashions. IQ responds in a very linear way, with an increasing number of revertants with increasing S9 up to 4 mg of protein per plate. Trp-P-2, on the other hand, shows a maximum response at 1 mg per plate and shows approximately half the response at 2 mg protein per plate for all the strains in which a positive response was seen. This confirms the finding of Nagao et al. (1981) and is very similar to the response for another aromatic amine 2-acetylaminofluorene (Felton et al., 1976). What differences in the metabolic pathways account for this difference in response to S9 concentration are not clear. [Pg.556]

In this series of bioassay experiments, several carcinogens failed to transform certain batches of hamster embryo cells, presumably because of a lack of endogenous enzymes required for the metabolic activation of these compounds. In short-term bacterial and mammalian cell mutagenesis systems, these enzymes are routinely provided by the addition of rat liver homogenates. As mentioned earlier, diethylnitrosamine and urethane, which failed to transform hamster embryo cells directly, were activated in a host-mediated in vivo-in vitro cell transformation assay in which the chemicals were inoculated intraperitoneally. In our laboratory, when A -2-acetylaminofluorene, 4-aminoazobenzene, auramine, diethylnitrosamine, 3-methoxy-4-aminoazoben-zene, Natulan, 2-nitrofluorene, p-rosaniline, and urethane were tested in the presence of hamster liver homogenates and appropriate cofactors, all except 4-aminoazobenzene gave positive results. The liver homogenates were prepared from hamsters that were not treated with enzyme inducers such as Aroclor 1254 or phenobarbital. [Pg.193]

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. [Pg.245]

McManus, M.E., W.M. Burgess, M.E. Veronese, A. Huggett, L.C. Quattrochi, and R.H. Tukey (1990). Metabolism of 2-acetylaminofluorene and benzo[a]pyrene and activation of food-derived heterocyclic amine mutagens by human cytochromes P-450. Cancer Res. 50, 3367-3376. [Pg.471]

The flavoprotein monooxygenase or MFMO enzyme is indicated to be present in sponges (Kurelec et al. 1985, 1987). Post-mitochondrial supernatants of G. cydonium, V. aerophoba, P. semitubulosa and T. aurantium readily activated (metabolized) 2-aminoanthracene (AA) to S. typhinurium TA98 mutagens in an NADPH-dependent reaction. T. aurantium also activated aminobiphenyl, 2-aminofluorene (AF) and 2-acetylaminofluorene (AAF). [Pg.62]

N-hydroxylation of 2-acetylaminofluorene occurs in man, monkey, dog, cat, rabbit, rat, mouse, and hamster, but not at all, or only in minimal amounts, in guinea-pigs or lemmings. In the case of 2-acetylaminofluorene, the N-hydroxy metabolites are considered to be active carcinogens. An alternate pathway of metabolism converts 2-acetylaminofluorene to the noncarcinogenic 7-hydroxy-2-acetylaminofluorene. The relative importance of the two pathways has been evaluated in various species and correlated with carcinogeniticy. The subject has been discussed recently [20, 25] and wiU not further be dealt with here. [Pg.145]

A first shortcoming is the possibility that mixed-function oxidases may not be the only enzymes involved in metabolism. For example, the most potent known derivative of 2-acetylaminofluorene is the sulphate ester and this derivative is only detected in the presence of sulphotransferases, which are not found in microsomes. In the second place, some mixed function oxidases will not be detected if the needed cofactors are not provided in sufficient amounts. Animal pretreatment conditions also affect enzyme activity. Thirdly, microsomes also perform reductions, hydrolyses and conjugations when the appropriate cofactors are provided. These functions could also be involved in enzymic activation and may be missed if the cofactors are not supplied. A fourth limitation of microsomal systems is that reactions observed in vitro may not occur in vivo and vice versa. The fifth... [Pg.256]


See other pages where Acetylaminofluorene metabolic activation is mentioned: [Pg.165]    [Pg.379]    [Pg.237]    [Pg.126]    [Pg.389]    [Pg.550]    [Pg.241]    [Pg.245]    [Pg.170]    [Pg.420]    [Pg.178]    [Pg.157]    [Pg.173]    [Pg.185]    [Pg.193]    [Pg.304]    [Pg.295]    [Pg.392]    [Pg.122]    [Pg.844]    [Pg.285]    [Pg.500]    [Pg.654]    [Pg.295]    [Pg.159]   
See also in sourсe #XX -- [ Pg.170 , Pg.171 ]




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