Contribution of the 5-Hydroxyl Group to the Mutagenicity of Mucochloric Acid

LaLonde, Robert T.; Perakyla, Hannu; Cook, Gary P.; Dence, C. W.

doi:10.1897/1552-8618(1990)9[687:cothgt]2.0.co;2

Cited by 16 publications

(35 citation statements)

References 6 publications

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“…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.…”

Section: Discussionsupporting

confidence: 88%

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

Kassie

Parzefall

Krönberg

et al. 1994

Environ and Mol Mutagen

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The genotoxic effects of three chlorohydroxyfuranones (CHFs), 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]-furanone (MX), 3-chloro-4-(chloromethyl)-5-hydroxy-2[5H]furanone (CMCF) and 3,4,-dichloro-5-hydroxy-2[5H]furanone (MCA), which are formed as byproducts of water disinfection with chlorine, were investigated in bacterial differential DNA repair assays in vitro and in animal-mediated assays in vivo. As indicators of DNA damage, E. coli K-12 strains were used that differ in their repair capacity (uvrB/recA vs. uvr+/rec+). Liquid incubation of the compounds without metabolic activation caused a pronounced reduction of the viability of the repair-deficient strain relative to the repair-proficient wild-type strain. The order of potency of genotoxic activity in vitro (dose range 0.004-10 micrograms/ml) was MX > CMCF > MCA. Addition of mouse S-9 mix or bovine serum albumin to the incubation mixtures resulted in an almost complete loss of the activity of all three test compounds. In the animal-mediated assays, mixtures of the indicator bacteria were injected intravenously into mice which were subsequently treated with the test compounds (200 mg/kg b.w.). Two hours later, the cells were recovered from various organs and the relative survival frequencies determined. Under these conditions, all three compounds caused pronounced genotoxic effects, MX and CMCF being stronger genotoxins than MCA. The strongest effects were consistently found in the gastrointestinal tract, but statistically significant DNA damage was also observed in indicator cells recovered from lungs, liver, spleen and kidneys. In a further experiment, the effects of lower doses of MX (4.3, 13 and 40 mg/kg) were investigated. In these experiments dose-dependent effects were measured in all organs. CMCF and MA caused only marginal effects at 40 mg/kg except in the stomach where approximately a 50% reduction of relative survival frequency was observed with CMCF. The results of these animal-mediated assays indicate that (i) all three CHFs cause genotoxic effects in the living animal, and (ii) the potencies of the three compounds observed under in vivo conditions are not commensurate with their extremely high activities measured in vitro. One possible explanation for the weaker responses observed in the animal-mediated assays might be that CHFs are inactivated by non-specific protein binding.

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Section: Discussionsupporting

confidence: 88%

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

Kassie

Parzefall

Krönberg

et al. 1994

Environ and Mol Mutagen

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“…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.…”

Section: His Reverse Mutation Assaysupporting

confidence: 92%

“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Mäki‐Paakkanen¹,

Komulainen²,

Krönberg

2004

Environ and Mol Mutagen

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The genotoxic responses of mixtures of four chlorohydroxyfuranones (CHFs), 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), 3,4-dichloro-5-hydroxy-2(5H)-furanone (MCA), 3-chloro- 4-(chloromethyl)-5-hydroxy-2(5H)-furanone (CMCF) and 3-chloro-4-methyl-5-hydroxy-2(5H)-furanone (MCF), were compared with the genotoxicity of the individual compounds. Genotoxicity was evaluated in the Salmonella reversion assay (Ames test), the in vitro Chinese hamster ovary (CHO) cell Hprt mutation assay, and in the CHO chromosome aberration test. When tested individually, the concentrations of the chemicals that were chosen for the mixtures induced no or only a modest increase in the genotoxic effects, and caused little or no cytotoxicity. In the Ames test, the genotoxic responses caused by the mixtures of CHFs did not follow simple additivity. Synergism was observed with strains TA97 and TA98, and antagonism with strain TA100. In the CHO/Hprt mutation assay, the mutagenic response of the mixtures was inconsistent, with near additivity seen with a mixture of CHFs that resulted in 12% cell survival. In contrast, the four CHFs together consistently caused more structural chromosome damage (mainly chromatid-type breaks and exchanges) compared to the sum of net effects of the four CHFs tested alone. Also, a potentiating effect was consistently seen for the cytotoxicity of the CHF mixtures both in the CHO/Hprt mutation assay and the chromosome aberration test. The present results indicate that the genotoxic effects of CHF mixtures can be greater than additive. Such effects may be worth considering in the cancer risk assessment of chlorinated drinking water.

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“…Relative to MX, for which several other genotoxic responses have now been recorded (13-17l, MCA was 100-1000-fold less mutagenic in the (TA100) assay (12,18). Also, MCA is -30-fold less mutagenic compared to RMX (10,12,18).…”

Section: Introductionmentioning

confidence: 92%

A study of inactivation reactions of N-acetylcysteine with mucochloric acid, a mutagenic product of the chlorination of humic substances in water

LaLonde¹,

Xie²

1992

Chem. Res. Toxicol.

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The Salmonella typhimurium (TA100) mutagenic compound, mucochloric acid [3,4-dichloro-5-hydroxy-2(5H)-furanone (MCA)], was inactivated by in vitro N-acetylcysteine (NAC). The reaction of MCA with NAC at pH7 was second order and gave products 4, 5, and 6a that resulted from the displacement of chlorine from C-3 or C-4 of MCA. The sodium borohydride treatment of product 4 gave the same product (7) as was obtained by treating 3,4-dichloro-2(5H)-furanone with NAC. The treatment of MCA with (R)-(+)-cysteine gave the bicyclic product 9a, in which the two chlorine atoms of MCA were still present. This product was slightly more mutagenic than MCA, whereas product 5 was less mutagenic than MCA and product 4 was nonmutagenic in the Salmonella typhimurium (TA100) assay.

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Contribution of the 5-Hydroxyl Group to the Mutagenicity of Mucochloric Acid

Cited by 16 publications

References 6 publications

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

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

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

A study of inactivation reactions of N-acetylcysteine with mucochloric acid, a mutagenic product of the chlorination of humic substances in water

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