skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Mutagenicity of N- and O-acetyl derivatives of methyl 3,4-diphenyl-5-hydroxylamino-2-furoate and n-hydroxy-4-aminobiphenyl in Salmonella typhimurium

Abstract

Methyl 3,4-diphenyl-5-hydroxylamino-2-furoate (N-OH-MDPF) (I), methyl 3,4-diphenyl-5-acetoxyamino-2-furoate (N-OAc-MDPF) (II), methyl 3,4-diphenyl-N-hydroxy-5-acetylamino-2-furoate (N-OH-MDPAF) (III), and methyl 3,4-diphenyl-N-acetoxy-5-acetylamino-2-furoate (N-OAc-MDPAF) (IV) were synthesized and tested for mutagenic activity for Salmonella typhimurium TA98 and TA100. The hydroxylamine (I) and acetyl derivatives (II - IV) did not show mutagenic activity in TA98 or TA100. In contrast, the parent nitro compound, methyl 3,4-diphenyl-5-nitro-2-furoate (MDPNF) (V) was found to be equally active in TA98 and TA98-DNP, and more active in TA100 and TA104. The mutagenic activity in TA100 and TA104 decreased significantly under anaerobic conditions. These data suggest that mechanisms involving O-acetylation of N-hydroxylamine to the acetoxyamine or acyl transfer reactions are not involved in the generation of mutagen from MDPNF. Furthermore, the differential mutagenic response of V in TA98 and TA98NR, its reduction to I, and the lack of activity of I suggest that the intermediates of reduction between the nitro and hydroxylamine, such as nitro or nitroso free radical anions, may be involved in mutagenesis. The decreased response of V under anaerobic conditions and increased response in TA104 suggest that secondary oxygen radicals generated from reduction intermediates may be responsible for the mutagenicity of MDPNF.

Authors:
; ;  [1]; ;  [2];  [3]
  1. (Univ. of Wisconsin, Madison (United States))
  2. (Josai Univ., Saitama (Japan))
  3. (Nagasaki Univ. Hospitals (Japan))
Publication Date:
OSTI Identifier:
6097926
Resource Type:
Journal Article
Resource Relation:
Journal Name: Environmental and Molecular Mutagenesis; (United States); Journal Volume: 17:2
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.; FURANS; DERIVATIZATION; HETEROCYCLIC COMPOUNDS; MUTAGEN SCREENING; REVERTANTS; MUTATION FREQUENCY; ANAEROBIC CONDITIONS; BIPHENYL; HYDROXYLAMINE; METABOLIC ACTIVATION; POLYCYCLIC NITRO COMPOUNDS; SALMONELLA TYPHIMURIUM; TRANSFERASES; AMINES; AROMATICS; BACTERIA; CHEMICAL REACTIONS; ENZYMES; HYDROCARBONS; MICROORGANISMS; MUTANTS; NITRO COMPOUNDS; ORGANIC COMPOUNDS; ORGANIC NITROGEN COMPOUNDS; ORGANIC OXYGEN COMPOUNDS; PROTEINS; SALMONELLA; SCREENING; 560300* - Chemicals Metabolism & Toxicology

Citation Formats

Swaminathan, S., Hatcher, J.F., Bryan, G.T., Yamamoto, Katsumi, Tanaka, Akira, and Ichikawa, Masataka. Mutagenicity of N- and O-acetyl derivatives of methyl 3,4-diphenyl-5-hydroxylamino-2-furoate and n-hydroxy-4-aminobiphenyl in Salmonella typhimurium. United States: N. p., 1991. Web. doi:10.1002/em.2850170204.
Swaminathan, S., Hatcher, J.F., Bryan, G.T., Yamamoto, Katsumi, Tanaka, Akira, & Ichikawa, Masataka. Mutagenicity of N- and O-acetyl derivatives of methyl 3,4-diphenyl-5-hydroxylamino-2-furoate and n-hydroxy-4-aminobiphenyl in Salmonella typhimurium. United States. doi:10.1002/em.2850170204.
Swaminathan, S., Hatcher, J.F., Bryan, G.T., Yamamoto, Katsumi, Tanaka, Akira, and Ichikawa, Masataka. Tue . "Mutagenicity of N- and O-acetyl derivatives of methyl 3,4-diphenyl-5-hydroxylamino-2-furoate and n-hydroxy-4-aminobiphenyl in Salmonella typhimurium". United States. doi:10.1002/em.2850170204.
@article{osti_6097926,
title = {Mutagenicity of N- and O-acetyl derivatives of methyl 3,4-diphenyl-5-hydroxylamino-2-furoate and n-hydroxy-4-aminobiphenyl in Salmonella typhimurium},
author = {Swaminathan, S. and Hatcher, J.F. and Bryan, G.T. and Yamamoto, Katsumi and Tanaka, Akira and Ichikawa, Masataka},
abstractNote = {Methyl 3,4-diphenyl-5-hydroxylamino-2-furoate (N-OH-MDPF) (I), methyl 3,4-diphenyl-5-acetoxyamino-2-furoate (N-OAc-MDPF) (II), methyl 3,4-diphenyl-N-hydroxy-5-acetylamino-2-furoate (N-OH-MDPAF) (III), and methyl 3,4-diphenyl-N-acetoxy-5-acetylamino-2-furoate (N-OAc-MDPAF) (IV) were synthesized and tested for mutagenic activity for Salmonella typhimurium TA98 and TA100. The hydroxylamine (I) and acetyl derivatives (II - IV) did not show mutagenic activity in TA98 or TA100. In contrast, the parent nitro compound, methyl 3,4-diphenyl-5-nitro-2-furoate (MDPNF) (V) was found to be equally active in TA98 and TA98-DNP, and more active in TA100 and TA104. The mutagenic activity in TA100 and TA104 decreased significantly under anaerobic conditions. These data suggest that mechanisms involving O-acetylation of N-hydroxylamine to the acetoxyamine or acyl transfer reactions are not involved in the generation of mutagen from MDPNF. Furthermore, the differential mutagenic response of V in TA98 and TA98NR, its reduction to I, and the lack of activity of I suggest that the intermediates of reduction between the nitro and hydroxylamine, such as nitro or nitroso free radical anions, may be involved in mutagenesis. The decreased response of V under anaerobic conditions and increased response in TA104 suggest that secondary oxygen radicals generated from reduction intermediates may be responsible for the mutagenicity of MDPNF.},
doi = {10.1002/em.2850170204},
journal = {Environmental and Molecular Mutagenesis; (United States)},
number = ,
volume = 17:2,
place = {United States},
year = {Tue Jan 01 00:00:00 EST 1991},
month = {Tue Jan 01 00:00:00 EST 1991}
}
  • The mutagenicities of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX, compound 1), 3-chloro-4-(dichloromethyl)-2(5H)-furanone (RMX, compound 6), and 2-(dichloromethyl)-3,3-dichloropropenal (TCB, compound 7) were determined in the same assay and in repetitive determinations using Salmonella typhimurium (TA 100) without microsomal fraction activation. In addition, the mutagenicity of 2-methyl-3,3-dichloropropenal (compound 8) was assayed in the same manner although not simultaneously with MX, RMX, and TCB. This study was undertaken to ascertain the role of open- and closed-ring forms of MX in the mutagenicity of MX. MX proved to be roughly 100 times more mutagenic than the open-ring analogue TCB and 10 times more mutagenic than the closed-ring analoguemore » RMX. Compound 8 was inactive. Assay stability of the three active compounds in Vogel-Bonner medium at 38{degree}C was estimated as the chemical half-life values by following the change in UV absorbance at selected wave lengths. The enhanced mutagenicity of MX relative to RMX and TCB is attributed to the intrinsic mutagenicity of MX and its grater stability is judged to play only a minor role.« less
  • Two chlorinated hydroxylated furanones, 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) and 3,4-(dichloro)-5-hydroxy-2(5H)-furanone (MA), are bacterial mutagens and they are also byproducts of chlorine disinfection, and frequent contaminants of drinking water. In this work MX is shown to induce nuclear anomalies in the gastrointestinal tract of the B6C3F1 mouse. The other chlorohydroxyfuranone, MA, gives suggestive evidence of activity. In this bioassay MX was approximately equivalent in potency to epichlorohydrin (ECH) but was much less potent than methylnitrosourea (MNU). The latter two chemicals are confirmed rodent gastrointestinal tract carcinogens. The duodenum was the most sensitive tissue responding with both increased numbers of nuclear anomalies per mousemore » and increased incidence of animals presenting the nuclear aberrations 24 h after a single oral dose of 0.37 mmol/kg{sup {minus}1} of MX. MA also induced a significant increase in duodenal nuclear anomalies. The proximal colon and forestomach responded to MX but not MA. This is the first study demonstrating that chlorohydroxyfuranones are capable of inducing nuclear toxicity in vivo. However, it is clear, for MX at least, that its potency in the gastrointestinal tract nuclear anomalies assay is not commensurate with its extreme bacterial mutagenicity.« less
  • The mutagenicity of pyrazole and seven pyrazole derivatives (4-nitropyrazole, 4-bromopyrazole, 1-methyl-4-nitropyrazole, 3,5-dimethyl-4-nitropyrazole, 1-methyl-4-bromopyrazole, 4,4'-dinitro-1, 1'-methylene-dipyrazole and 4,4'-dibromo-1,1'-methylene-dipyrazole) has been investigated with the L-arabinose forward mutation assay of Salmonella typhimurium. Two nitroimidazoles (1-methyl-5-nitroimidazole and metronidazole) were included as reference drugs. The mutagenicity of each chemical was determined by both preincubation and liquid tests, in the presence or absence of S9 microsomal fraction. The mutagenic responses was expressed as the absolute number of L-arabinose resistant mutants growing in selective plates, supplemented with traces of D-glucose. Strain BA13 with a wild-type lipopolysaccharide barrier was used as a comparison to the deep rough derivativemore » BA9. No mutagenic effect was detected with pyrazole and two of its derivatives, 1-methyl-4-bromopyrazole and 4,4'-dibromo-1,1'-methylene-dipyrazole. The other five pyrazole derivatives were mutagenic to different degrees, although their mutagenic potencies were always considerably lower than those of the two nitroimidazoles. The results suggest that 4-nitropyrazoles, as well as 4,4'-dinitro-1, 1'-methylene-dipyrazoles, should be investigated further as alternatives to, or even substitutes for, the currently used nitroimidazoles.« less