This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lee, M.-S. Articles by Isobe, M. Search for Related Content PubMed PubMed Citation Articles by Lee, M.-S. Articles by Isobe, M.

Metabolic Activation of the Potent Mutagen, 2-Naphthohydroxamic Acid, in Salmonella typhimurium TA98¹

Department of Chemical Carcinogenesis, Michigan Cancer Foundation, Detroit, Michigan 48201

The objective of the present study was to explore the mechanisms responsible for the strong, direct-acting mutagenicity of 2-naphthohydroxamic acid (NHA) for Salmonella typhimurium TA98. NHA was converted to its O-acetate (O-Ac-NHA) by acetyl-CoA, in the presence of competent or heat-treated cell-free bacterial preparations. O-Ac-NHA, which is more mutagenic than NHA, reacted nonenzymatically with tRNA in neutral solutions with retention of both the naphthyl and carbonyl groups in the products, but NHA did not react. Enzymatic sulfate conjugation was not demonstrated. TA98 cells converted NHA to 2-aminonaphthalene, presumably through a Lossen rearrangement following O-acetylation or conjugation by other metabolic pathways. TA98 cells reduced O-Ac-NHA to 2-naphthamide, and NADH and NADPH were shown to be cofactors for reduction in the presence of a cell-free bacterial preparation. Although horseradish peroxidase and H₂O₂ catalyzed the binding of these compounds to tRNA, no evidence of oxidation of NHA or O-Ac-NHA was obtained with H₂O₂ and cell-free preparations of TA98 or the cells themselves, as judged by the lack of formation of the peroxidative product, 2-naphthoic acid. Both NHA and O-Ac-NHA reacted with DNA of TA98 with retention of both naphthyl group and carbonyl of the naphthoyl moiety in the adduct(s). These results suggest that NHA may be activated in TA98 by esterification, and the resulting metabolites may amidate or carbamoylate nucleic acids.

¹ This work from the A. Alfred Taubman Facility was supported by NIH Grant CA-37885 and an institutional grant from the United Foundation of Detroit.

² To whom requests for reprints should be addressed.

³ Present address: Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotage-cho, Hirakata, Osaka, Japan.

Received 7/28/89. Accepted 4/ 3/90.