N-Hydroxy-2-acetylaminofluorene

Small Quantities. Wear goggles, rubber gloves, and protective clothing. Work in the fume hood. To 0.25 g of N-hydroxy-2-acetylaminofluorene in a 50-mL round-bottom flask, add 10 mL of concentrated hydrochloric acid. Fit the flask with a condenser and heat under reflux for at least 10 hours. Cool the contents of the flask to 0°C in an ice-salt bath 

Armour, M.A., Browne, L.M., and Weir, G.L., J. Chem. Educ., 62, A93, 1985 Armour, M.A., J. Chem. Educ., 65, A64, 1988 Armour, M.A., Disposal methods for some known or suspect carcinogens, in Recent Advances of Chemistry and Molecular Biology in Cancer Research, Dai, Q., Armour, M.A., and Zheng, Q., Eds., Springer-Verlag, Heidelberg, 1993, p. 315. 

3-Bis(2-chloroethyl)tetrahydro-2H-l,3,2-oxazaphosphorin-2-amine-2-oxide, 3(2-chloro-ethyl) -2- [ (2-chloroethyl) amino]tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide, iphosphamide, NSC-109724.1 

Soluble in water and carbon disulfide very soluble in dichloromethane sensitive to hydrolysis, oxidation, and heat.2 

Most common and serious toxicity to patients includes low blood count, as well as vomiting, nausea, loss of hair, water retention, and cardiac damage.3 LD50 in rats, 160 mg/kg.1 

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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. 

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. 

Meerman JHN, Nijland C, Mulder GJ. 1987. Sex differences in sulfation and glucuronidation of phenol, 4-nitrophenol and N-hydroxy-2-acetylaminofluorene in the rat in vivo. Biochem Pharmacol 36 2605-2608. 

Inaba T, Kovacs J (1989) Haloperidol reductase in human and guinea pig livers. Drug Metab Dispos 17 330-333 Lewis AJ, Otake Y, Wafie UK, Walle T (2000) Sulphona-tion of N-hydroxy-2-acetylaminofluorene by human dehydroepiandrosterone sulphotransferase. Xenobiotica 30 253-261... 

Nagata, K., Ozawa, S., Miyata, M., Shimada, M., Gong, D. W., Yamazoe, Y., and Kato, R. (1993) Isolation and expression of a cDNA encoding a male-specific rat sulfotransferase that catalyzes activation of N-hydroxy-2-acetylaminofluorene. J. Biol. Chem. 268, 24720-24725. 

Corbett, M. D., L. O. Lim, B. R. Corbett, J. J. Johnston and P. Wiebkin. 1988. Covalent binding of N-hydroxy-2-acetylaminofluorene and N-hydroxy-2-glycolylaminofluorene to rat hepatocyte DNA In vitro and cell-suspension studies. Chem. Res. Toxicol. 1 41-46. 

Lim, L. O., B. R. Corbett and M. D. Corbett. 1987. Irreversible inhibition of the cytosolic metabolism of N-hydroxy-2-acetylaminofluorene by its glycolyl analog. Cancer Lett. 37 205-211. 

Mangold, B. L. K., J. Erickson, C. Lohr, D. J. McCann and J. B. Mangold. 1990. Self-catalyzed irreversible inactivation of rat hepatic aryl sulfotransferase IV by N-hydroxy-2-acetylaminofluorene. Carcinogenesis 11 1563-1567. 

Ringer, D. R, T. R. Norton and R. R. Self. 1992. Reaction product inactivation of aryl sulfotransferase IV following electrophilic substitution by the sulfuric acid ester of N-hydroxy-2-acetylaminofluorene. Carcinogenesis 13 107-112. 

On the other hand, a few drugs and a number of xenobiotic aromatic amines are known to be A -hydroxyl-ated and then 0-glucuronidated. The reactivity of N-0-glucuronides, such as //-hydroxy-2-acetylaminofluorene glucuronide (Fig. 31.37) leads to heterolytic decomposition into a //-acetyl-A -arylnitrenium ion which then reacts with nucleic acids and proteins. ... 

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. 

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. 

Deacetylase activity towards A -hydroxy-acetylaminofluorene (OH-AAF) was indicated to be absent in digestive gland microsomes of M. galloprovincialis (Kurelec and Krca 1987), but present in M. edulis towards AAF and N-acetyl-O toluidine (see Sect. 7.2.2). 

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