Effects of phorone and/or buthionine sulfoximine on teratogenicity of 5-fluorouracil in mice.

Embryotoxicity and teratogenicity of 5-fluorouracil (5-FU) and modulation of its effect by the depletors of glutathione (GSH) were evaluated in mice. Pregnant ICR mice were intraperitoneally (i.p.) injected with 25 mg/kg of 5-FU on day 11 of gestation (vaginal plug = day 0). Mice were pretreated i.p. with 250 mg/kg of phorone, a GSH depleting agent and/or 200 mg/kg of buthionine sulfoximine (BSO, an inhibitor of GSH biosynthesis) 4 hours before dosing with 5-FU. Dams were killed on day 17 of gestation. Fetuses were examined for external malformations, especially limb malformations. Pretreatment with phorone or BSO decreased fetal weight and increased the frequency and severity of oligodactyly induced by 5-FU, as well as the reduction of maternal GSH levels. Combined use of 125 mg/kg phorone and 100 mg/kg BSO i.p. augmented growth retardation induced with 5-FU. Cotreatment with exogenous GSH, at a dose of 300 mg/kg injected intravenously, could not suppress the augmentative effects of phorone and/or BSO on 5-FU teratogenicity under these experimental conditions. These results indicate that the level of endogenous GSH is one of the factors which significantly affects teratogenicity of 5-FU.