Metabolic Activation of N-Hydroxy Compounds by Conjugation

Abstract

1. Conjugation of N-hydroxy-N-arylacetamides results in the metabolic activation of this class of compounds.

2. This paper reviews current knowledge of these reactions with emphasis on the involvement of conjugates of N-hydroxy compounds in the mechanism of action of carcinogenic N-arylacetamides.

3. The glucuronide and sulphate conjugates of the carcinogen N-hydroxy-2-acetylaminofluorene react in vitro with protein, RNA and DNA, leading to the covalent attachment of 2-acetylaminofluorene and 2-aminofluorene residues to these macromolecules.

4. The most reactive groups in proteins and nucleic acids are methionine, cysteine, tryptophan, tyrosine and guanine or deoxyguanine.

5. There are major differences in the reactions of the glucuronide and the sulphate conjugates of N-hydroxy-N-arylacetamides with tissue nucleophiles, mainly in the rate of reaction and in the kind of products formed.

6. The structure of the aryl group in a conjugate of an N-hydroxy-N-arylacetamide also has a marked effect on the nature and extent of reactivity, with the fluorenyl derivatives generally being most reactive.