ACYLTRANSFERASE-MEDIATED BINDING OF N-HYDROXYARYLAMIDES TO NUCLEIC-ACIDS

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  • 1 January 1980
    • journal article
    • research article
    • Vol. 40  (3) , 834-840
Abstract
N-Hydroxyarylamides are metabolically activated to nucleic acid-binding species by the action of N,O-acyltransferase (AT). The substrate specificity of these enzymes in rat, guinea pig, monkey, baboon, pig and human liver was examined by measuring the AT-mediated nucleic acid binding of the N-formyl, N-acetyl and N-propionyl derivatives of N-hydroxy-2-aminofluorene. Human and pig enzymes catalyzed binding in the order formyl .mchgt. acetyl > propionyl, while for the other species the order was acetyl > propionyl > formyl. Ammonium sulfate fractionation of the cytosols suggested that the baboon and rat have at least 2 different AT: 1 with a higher specificity for the formyl derivative, the other with a marked preference for acetyl and propionyl compounds. Only 1 form, with a high formyl group specificity, was detected from human liver. The identity of the in vitro AT-mediated DNA adducts from rat, baboon and human liver was established. In each instance, 1 adduct accounted for > 75% of the bound 2-aminofluorene (AF) residues. This product had a high-pressure liquid chromatography retention time and pH-dependent partition characteristics identical to those of an adduct synthesized by an acid-dependent (pH 4.6) reaction of N-hydroxy-2-aminofluorene with calf thymus DNA. This synthetic adduct was identified as N-(deoxyguanosin-8-yl)-2-aminofluorene by NMR, mass and UV light spectroscopy. It was identical to the product obtained from the alkaline (pH 12) hydrolysis of N-(deoxyguanosin-8-yl)-2-acetylaminofluorene. Since an arylaminated (i.e., aminofluorene) residue(s) is the major product found in rat liver DNA following administration of N-hydroxy-N-acetyl-2-aminofluorene, AT may play a major role in the formation of this DNA-carcinogen adduct.