DNA strand breaks induced in cultured human and rodent cells by chlorohydroxyfuranones--mutagens isolated from drinking water.
Chlorohydroxyfuranones, by-products of chlorine disinfection and drinking water contaminants, are shown to produce DNA strand breaks in human and rodent cells. One chlorohydroxyfuranone, 3-chloro-4-dichloromethyl-5-hydroxy-2[5H]-furanone (MX), a potent bacterial mutagen, induces 232 +/- 89 DNA strand breaks.(cell-microM)-1 in human CCRF-CEM cells over a concentration range of 4.4 to 220 microM. This constitutes a DNA damage potency comparable to dimethylsulfate (DMS). By comparison, 3,4-dichloro-5-hydroxy-2[5H]-furanone (MA), another chlorohydroxyfuranone which is approximately four orders of magnitude less mutagenic than MX in Salmonella typhimurium strain TA100, is only about tenfold less potent as an inducer of DNA strand breaks in these cells, i.e., 18.2 +/- 3.1 strand breaks.(cell-microM)-1. The DNA strand-breaking potential of MX is inactivated by prior incubation with a rat liver S9 homogenate. In addition, both chlorohydroxyfuranones are ineffective at producing DNA strand breaks in primary rate hepatocytes (PRH) at concentrations below those which produce cytotoxicity as assessed by release of the cellular enzyme lactate dehydrogenase (LDH). Prior treatment of the PRH with 750 microM diethyl maleate, a glutathione-depleting agent, did not enhance the cytotoxicity nor the DNA strand-breaking potential of either chlorohydroxyfuranone. This could indicate that glutathione-glutathione-S-transferase is not an important mechanism for the detoxification of these compounds in PRH.
Biochemical and Molecular Toxicology Branch, Laboratory, U.S. Environmental Protection Agency, Cincinnati, Ohio 45268.
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LW
Chang
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Daniel
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DeAngelo
D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000187:drug effects*; D005663:Furans / Q000302:isolation & purification / Q000494:pharmacology*; D005978:Glutathione / Q000502:physiology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects; D008298:Maleates / Q000494:pharmacology; D009153:Mutagens / Q000494:pharmacology*; D051381:Rats; D014874:Water Pollutants, Chemical / Q000494:pharmacology*
D005663:Furans; D008298:Maleates; D009153:Mutagens; D014874:Water Pollutants, Chemical; C067157:3,4-(dichloro)-5-hydroxy-2(5H)-furanone; C054121:3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone; D004247:DNA; C014476:diethyl maleate; D005978:Glutathione