Production of unscheduled DNA synthesis in rodent hepatocytes in vitro, but not in vivo, by 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]-furanone (MX).
Incubation of both rat and mouse hepatocytes with 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]-furanone (MX) in vitro resulted in a dose-dependent increase in unscheduled DNA synthesis (UDS) at sub-cytotoxic concentrations (1-10 microM MX; 20 h incubation). Depletion of glutathione stores by pre-treatment of rat hepatocytes with buthionine sulfoximine did not result in a significant increase in UDS produced by MX. In contrast, MX did not induce UDS in mouse hepatocytes ex vivo either 3 or 16 h following administration of a single oral dose of 100 mg/kg MX. Despite the ability of MX to produce repairable DNA damage, restricted access of MX to the liver may prevent a measurable UDS response in vivo.
Nunn
J W
JW
School of Biochemistry, University of Birmingham, Edgbaston, UK.
Davies
J E
JE
Chipman
J K
JK
D000284:Administration, Oral; D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009153:Mutagens / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D005663:Furans; D009153:Mutagens; D019328:Buthionine Sulfoximine; C054121:3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone; D004247:DNA; D005978:Glutathione