Preventive action of thioethers towards in vitro DNA binding and mutagenesis in E. coli K12 by alkylating agents.
Thioethers are effective scavengers of electrophilic metabolites derived from the hepatocarcinogen N-hydroxy-2-acetylaminofluorene (van den Goorbergh et al., 1987). In this study 2 of these thioethers, 4-(methylthio)benzoic acid (MTB) and its methylester, methyl 4-(methylthio)benzoate (MMTB), have been tested for their ability to prevent in vitro DNA binding and mutation induction in E. coli K12 by the direct alkylating agents ethylnitrosourea (ENU), methylnitrosourea (MNU), ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS). In addition to MTB and MMTB, the thioether L-methionine (Met), and the thiols glutathione (GSH) and L-cysteine (Cys) were included for reasons of comparison. MTB was able to (partially) prevent DNA binding and mutation induction by ENU. However, this thioether was ineffective with EMS. DNA binding and mutagenesis by EMS were (partially) prevented by GSH and Cys, while these thiols could not prevent DNA binding and mutation induction by ENU. MMTB was unable to prevent mutation induction by these ethylating agents. With the methylating agents, similar effects of MTB were observed: MTB effectively prevented mutation induction by MNU while it was much less effective towards MMS. GSH and Cys were comparably effective as antimutagenic agents towards both methylating agents. Met was unable to prevent either DNA binding or mutation induction by these agents. Taken together, the results show that aromatic thioethers are able to trap genotoxic electrophiles derived from the nitrosoureas ENU and MNU, and may therefore act as potential anticarcinogens towards these agents, which are only poorly detoxified by GSH.
Kroese
E D
ED
Laboratory of Carcinogenesis and Mutagenesis, National Institute of Public Health and Environmental Protection, Bilthoven, The Netherlands.
Zeilmaker
M J
MJ
Mohn
G R
GR
Meerman
J H
JH
D000477:Alkylating Agents / Q000378:metabolism / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics; D005020:Ethyl Methanesulfonate / Q000494:pharmacology; D005038:Ethylnitrosourea / Q000378:metabolism / Q000494:pharmacology; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D008770:Methylnitrosourea / Q000494:pharmacology; D009152:Mutagenicity Tests; D013440:Sulfides / Q000494:pharmacology*
D000477:Alkylating Agents; D001565:Benzoates; D013440:Sulfides; C066074:4-(methylthio)benzoic acid; C051442:methyl 4-(methylthio)benzoate; D008770:Methylnitrosourea; D004247:DNA; D005020:Ethyl Methanesulfonate; D008741:Methyl Methanesulfonate; D005038:Ethylnitrosourea