Synthesis of the O-glucuronide of N-2-fluorenylhydroxylamine. Reaction with nucleic acids and with guanosine 5'-monophosphate

Abstract

O-Glucuronides of arylhydroxylamines have not been previously reported in the literature. The facile removal of the AT-acetyl group from sodium (N-acetyl-A-2-fluorenylhydroxylamine /3-D-glucosid)uronate has led to the synthesis of sodium (AT-2-fluorenylhydroxylamine /3-D-glucosid)uronate. This latter glucuronide is unstable in aqueous solutions, decomposing completely within several minutes; the products of the decomposition have not yet been characterized. Sodium (Ar-2-fluoren-9-14C-ylhydroxylamine (J-D-glucosid)uronate has been synthesized and the compound reacts with RNA and DNA in vitro, resulting in the covalent binding of radioactivity to the nucleic acids. This glucuronide reacts with guanosine 5'-monophosphate to give 8-(tV-2-fluorenylamino)guanosine 5 '-monophosphate, but does not react with the 5'-monophosphates of uridine, cytidine, or adenosine. It is proposed that the O-glucuronide of 7V-2-fluorenylhydroxylamine might be formed as an intermediate metabolite of the carcinogen A'-acetyl-A'-2-fluorenylhydroxylamine, thus accounting, at least in part, for the observed binding of this carcinogen to rat liver DNA in vivo.

N-Acetyltransferase Phenotype and Risk in Urinary Bladder Cancer: Approaches in Molecular Epidemiology. Preliminary Results in Sweden and Denmark

“…By analogy, one might expect that esterification of N-hydroxyarylamines would give rise to electrophilic metabolites. Indeed, the N-O-glucuronide conjugate of N-hydroxy-2-aminofluorene, when generated in vitro, represents an extremely potent electrophile (48,49), although such compounds have yet to be demonstrated as in vivo metabolites. Alternatively, the N-glucuronides of N-hydroxyarylamines (Fig.…”

Some historical aspects of N-aryl carcinogens and their metabolic activation.

“…The glucuronide of N-hydroxy-AAF, which is a major metabolite (60,83,84), has weak electrophilic reactivity at neutral pH (85,86). The extent of reaction of the glucuronide increases very rapidly with small increases in pH; this increase in activity apparently results from loss of the N-acetyl group and the markedly greater reactivity of the glucuronide of N-hydroxy-AF as compared to that of Nhydroxy-AAF (87). The next metabolic pathway to be identified was the sulfotransferase reaction for the formation of N-sulfonoxy-AAF (88,89).…”

Characterization of covalent binding of [14C]‐2‐chloro‐4‐acetotoluidide to microsomes of starling liver and kidney

“…In addition, the starling kidney possesses a high N-deacetylase activity in the mitochondria and microsomes where the highest concentration of [14C]-CAT binding occurs (3,6). Deacetylation by the kidney of a glucuronide conjugate formed in the liver could possibly make the compound very reactive as reported for similar compounds such as N-hydroxyacetaminofluorene-N-0-glucuronide (34). The reactive molecule could then bind with tissue nucleophiles leading to toxicity.…”