Production of unscheduled DNA synthesis in rodent hepatocytes in vitro, but not in vivo, by 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5 H]-furanone (MX)

Abstract

Incubation of both rat and mouse hepatocytes with 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5 H]-furanone (MX) in vitro resulted in a dose-dependent increase in unscheduled DNA synthesis (UDS) at sub-cytotoxic concentrations (1–10 μM 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.