Effect on mutagenicity of the stepwise removal of hydroxyl group and chlorine atoms from 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone: carbon-13 NMR chemical shifts as determinants of mutagenicity

Abstract

The response of mutagenicity to the stepwise replacement of chlorine atoms and the hydroxyl group by hydrogen in 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX, 1) was determined in several assays by using Salmonella typhimurium tester strain (TA100). In all, eight MX derivatives were assayed. Several were studied together in at least one assay. In addition to MX, the seven included 3-chloro-4-(dichloromethyl)-2(5H)-furanone (RMX, 2), 3-chloro-4-(chloromethyl)-5-hydroxy-2(5H)-furanone (3), 3-chloro-4-(chloromethyl)-2(5H)-furanone (4), 4-(chloromethyl)-5-hydroxy-2(5H)-furanone (5), 4-chloromethyl-2(5H)-furanone (6), and 4-(dichloromethyl)-2(5H)-furanone (8). Compounds 1-6 were mutagenic. Compound 8 gave erratic results. 4-(Acetoxymethyl)-2(5H)-furanone (11) was nonmutagenic. The largest drop in mutagenicity amounted to a factor of about 10(2) for the replacement of the hydroxyl group or a C-3 chlorine atom from 3. Other replacements of the hydroxyl group or a C-3 or C-6 chlorine atom amounted to mutagenicity diminished by a factor of only 10. On the basis of the rates of UV spectral changes under assay conditions, chemical half-life values (ct 1/2) for 1-6 and 8 were estimated as indicators of compound stability. However, mutagenicity differences were shown to result principally from the intrinsic mutagenicities of the six compounds 1-6 rather than from differences in stability.(ABSTRACT TRUNCATED AT 250 WORDS)

Induction of genotoxic effects by chlorohydroxyfuranones, byproducts of water disinfection, in E. coli K‐12 cells recovered from various organs of mice

“…Our findings show that the compounds are also extremely potent genotoxins in E. coli assays that detect repairable DNA damage. The results of the present in vitro tests are in good agreement with findings obtained with Salmonella in that the ranking order of genotoxicity of the compounds is identical in both systems, LaLonde et al, 1990bLaLonde et al, , 1991Kronberg and Franzen, 19931. In both test systems, addition of liver S-9 resulted in a strong reduction of their genotoxic potencies [Meier et al, 1987b;Lampleo et al, 1989;Ishiguro et al, 1987;Holmbom et al, 19841.…”

Brominated analogs of 3‐chloro‐4‐(dichloromethyl)‐5‐hydroxy‐2(5H)‐furanone: Preparation of 3‐chloro‐4‐(bromochloromethyl)‐5‐hydroxy‐2(5H)‐furanone and mutagenicity studies

“…Mutagenic potencies observed for MX with TA100 in freshly synthesized products resulted in 3,467 revertants/nmol, which is within the order of magnitude reported by other authors [3,24,25]. Interestingly, the bromo derivatives elicited a significant increase in mutagenic potency with respect to MX, and this potency was proportional to the presence of one, two, or three bromine atoms replacing the chlorine atoms in MX (cf., Fig.…”

“…1). This furanone is a potent direct‐acting mutagen in the Salmonella typhimurium assay [1–5]. The MX has been detected in chlorine‐disinfected drinking water samples and the data available indicate that this compound is originated from the reactions of chlorine with the humic substances not eliminated during the purification of raw water [2,6,7].…”

Bacterial and mammalian‐cell genotoxicity of mixtures of chlorohydroxyfuranones, by‐products of water chlorination

“…There was no marked difference in the mutagenic potency between MCA and MCF (Table I). This is consistent with earlier published data; compared to MX, the three other CHFs are less potent mutagens in bacteria [Meier et al, 1986[Meier et al, , 1987aIshiguro et al, 1988;LaLonde et al, 1990LaLonde et al, , 1991Kronberg and Franzén, 1993;Niittykoski et al, 1995;Knasmüller et al, 1996;Franzén et al, 1998;Shaughnessy et al, 2000]. The positive controls used in the Ames test gave a clear increase in revertant colonies.…”

“…The genotoxicities of the CHFs, MX, MCA, CMCF and MCF, are well known. The data on the induction of gene mutations in bacteria and in mammalian cells, and on the induction of DNA and chromosome damage in mammalian cells by the CHFs, show that there are differences in the genotoxic potency of these chemicals [Meier et al, 1986[Meier et al, , 1987aIshiguro et al, 1988;LaLonde et al, 1990LaLonde et al, , 1991Kronberg and Franzén, 1993;Niittykoski et al, 1995;Knasmüller et al, 1996;Franzén et al, 1998;Le Curieux et al, 1999;Shaughnessy et al, 2000;Mäki-Paakkanen et al, 2001a,b]. However, the maximum effect observed in the alkaline Comet assay and the chromosome aberration test with CHO cells was similar for the four compounds [Mäki-Paakkanen et al, 2001a].…”