DNA strand breaks induced in cultured human and rodent cells by chlorohydroxyfuranones—mutagens isolated from drinking water

摘要

AbstractChlorohydroxyfuranones, 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‐μM)−1in human CCRF‐CEM cells over a concentration range of 4.4 to 220 μM. 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 inSalmonella typhimuriumstrain 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‐μM)±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 μM 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 mecha