Atsushi Hakura

Formation of 8-hydroxyguanine residues in DNA treated with 4-hydroxyaminoquinoline 1-oxide and its related compounds in the presence of seryl-AMP

The mechanism whereby treatment of DNA with 4-hydroxyaminoquinoline 1-oxide (4HAQO) in the presence of seryl-AMP leads to the formation of 8-hydroxyguanine (8-OH-Gua) residues in DNA (Kohda et al., this journal, 139, 626, 1986) has been studied. In the survey of other N-arylhydroxylamines, only 4HAQO analogues which could bind to DNA produced 8-OH-Gua. The amount of 8-OH-Gua varied depending on the structure of 4HAQO analogues and that of DNA. The formation of 8-OH-Gua was not inhibited by active oxygen scavengers. Possible mechanisms are discussed.

Mutagenicity of pyridine- and quinoline-carbohydroxamic acid derivatives

11 pyridine- and 6 quinoline-carbohydroxamic acids were tested for mutagenicity on Salmonella typhimurium TA100 and TA98. The results are compared with those obtained for benzohydroxamic acid and 4 naphthohydroxamic acids. Most of them were mutagenic on both these tester strains. Of the pyridine derivatives, pyridine-2-carbohydroxamic acid was the most potent mutagen. Quaternarization of the pyridine-ring nitrogen prevented the induction of mutation to a marked extent. Among the quinoline derivatives, quinoline-6-carbohydroxamic acid showed potent mutagenicity similar to that of 2-naphthohydroxamic acid. The present study supports the proposal made previously that the mechanism for mutagenicity of hydroxamic acids involves Lossen rearrangement of the acid conjugates produced by enzymic acylation (or perhaps phosphorylation or sulfation) of the hydroxamic acids, followed by carbamoylation of the target molecule in the cell by the resultant isocyanate. The multiplicity of factors determining the mutagenic potency of hydroxamic acids is discussed.

Studies on chemical carcinogens and mutagens. XXVII: Alkylating property of mutagenic N-trimethylsilylmethyl-N-nitrosourea, a silicon-analogue of N-neopentyl-N-nitrosourea, in aqueous media

Abstract The kinetics for hydrolysis and the chemoselectivity toward nucleophiles of mutagenic N-trimethylsilylmethyl-N-nitrosourea, a silicon analogue of N-neopentyl-N-nitrosourea, were studied.

XXIX. Mutagenic N-trimethylsilylmethyl-N-nitrosourea as a biological alkylating agent equivalent to N-methyl-N-nitrosourea (MNU)

N-Trimethylsilylmethyl-N-nitrosourea (TMS-MNU), a silicon analogue of N-neopentyl-N-nitrosourea (neoPNU), was assayed for mutagenicity and/or cytotoxicity on a series of E. coli B tester strains, S. typhimurium TA100, Chinese hamster V79, and cultured murine leukemia L1210 cells. All the biological activities demonstrated in this study reveal that this nitrosourea is a biological methylating agent equivalent to N-methyl-N-nitrosourea (MNU) but definitely distinguished from all the other alkylnitrosoureas examined so far, including neoPNU (the carbon analogue of TMS-MNU). The proposed molecular mechanism is that trimethylsilylmethanediazohydroxide is produced by hydrolytic activation of TMS-MNU and undergoes a nucleophilic cleavage of the Si--CH2 chemical bond at a high rate to form methanediazohydroxide (the reactive intermediate of MNU) which, in turn, methylates the informational biopolymer leading to mutagenesis.

Inhibitory effect of heavy water on mutability of chemically injured Escherichia coli cells

After E. coli cells (WP2 and WP2uvrA) were treated with chemical mutagens (methyl methanesulfonate, MMS; N-methyl-N-nitrosourea, MNU; 4-nitroquinoline 1-oxide, 4NQO) in 1/15 M phosphate buffer, the mutability of the treated cells plated on a D2O-agar plate was compared with that plated on an ordinary H2O-agar plate. The mutation frequency decreased more or less on the D2O-agar plate. The D2O-substitution effects, as termed by the relative mutation frequencies (MFD2O/MFH2O), are 0.92 for MMS, 0.29 for MNU, and 0.42 for 4NQO in WP2, and 0.68 for MMS, 0.49 for MNU, and 0.16 for 4NQO in WP2uvrA. The D2O effect seemed to be partly related to the function of the uvrA gene-associated products. The pH dependence of mutability was discussed in connection with the D2O-substitution effect.