Genotoxic effects of the drinking water mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]-furanone (MX) in mammalian cells in vitro and in rats in vivo.
The potent bacterial mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]- furanone) (MX), which is formed during chlorination of drinking water and accounts for about one third of the Ames mutagenicity of tap water, has been studied with respect to its genotoxicity in vitro and in vivo. Treatment with 30-300 microM MX (1 h) induced DNA damage in a concentration-dependent manner in suspensions of rat hepatocytes, as measured by an automated alkaline elution system. The effect was similar in hepatocytes from PCB-induced and uninduced rats. DNA damage was induced in V79 Chinese hamster cells and in isolated rat testicular cells, at the same concentration level as in hepatocytes. Pretreating testicular cells with diethylmaleate, which depletes 85% of cellular glutathione, had no significant effect on the DNA damage induced by MX. The treatment conditions used in the alkaline elution experiments were not cytotoxic to any of the cell types used, as determined by trypan blue exclusion. V79 cells exposed to 2-5 microM MX (2 h) showed an increased frequency of sister-chromatid exchanges (SCE) whereas no significant effect on HGPRT mutation induction was observed. Higher concentrations (greater than 10 microM, 2 h) apparently blocked cell division. The data indicate that MX can react directly with DNA or that MX is metabolized to an ultimate mutagen via some enzyme which is common in mammalian cells. The in vivo experiments showed no evidence of genotoxicity after intraperitoneal (18 mg/kg, 1 h) or oral (18, 63 or 125 mg/kg, 1 h) administration of MX, as measured by alkaline elution, in any of the following organs: the pyloric part of the stomach, the duodenum, colon ascendens, liver, kidney, lung, bone marrow, urinary bladder and the testes. In conclusion, MX is a direct-acting genotoxicant in vitro but no in vivo genotoxicity was detected.
Brunborg
G
G
National Institute of Public Health, Department of Environmental Medicine, Oslo, Norway.
Holme
J A
JA
Søderlund
E J
EJ
Hongslo
J K
JK
Vartiainen
T
T
Lötjönen
S
S
Becher
G
G
D015112:4-Nitroquinoline-1-oxide / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000633:toxicity*; D005978:Glutathione / Q000494:pharmacology; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects; D008297:Male; D016297:Mutagenesis, Site-Directed; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D012854:Sister Chromatid Exchange / Q000187:drug effects; D013270:Stomach / Q000187:drug effects; D013737:Testis / Q000187:drug effects
D005663:Furans; D009153:Mutagens; D015112:4-Nitroquinoline-1-oxide; C054121:3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone; D004247:DNA; D007041:Hypoxanthine Phosphoribosyltransferase; D005978:Glutathione