Effects of Glutathione and Related Compounds on Teratogenicity of 5-Fluorouracil or Cadmium Hydrochloride in Mice*

Glutathione (GSH) is a tripeptide consisting of cysteine, glutamic acid and glycine, and plays an important role in detoxification reactions. In this report, we describe (1) the effects of the depleting agents of GSH such as diethylmaleate (DEM), phorone, and buthionine sulfoximine (BSO) on teratogenicity of 5-fluorouracil (5-FU) in mice, (2) the effects of GSH or N-acetyl-L-cysteine (NAC), a precursor of GSH on teratogenicity of 5-FU or cadmium hydrochloride (Cd) in mice. Pregnant ICR mice were injected intra-peritoneally (i.p.) with 5-FU at dose levels of 20, 25, and 30 mg/kg on day 11 of gestation (vaginal plug = day 0). Mice were injected i.p. with DEM, phorone, or BSO 4 to 6 hours before dosing with 5-FU. Mice were also pretreated intravenously (i.v.) with GSH at dose levels of 150, 300 and 600 mg/kg, or NAC at dose levels of 80, 160, and 320 mg/kg 0.5 to 2 hours before dosing with 5-FU. In the Cd-teratogenicity study, mice were injected i.v. with GSH or NAC before dosing with Cd at 3.5 mg/kg i.p. on day 11 of gestation. Pretreatment with DEM, phorone or BSO increased the incidence of oligodactyly induced by 5-FU, while pretreatment with GSH or NAC decreased the incidences. Pretreatment with GSH or NAC decreased the incidence of cleft palate and abnormal palatal rugae induced by Cd. The results suggest that cysteine plays a key role in the teratogenicity of 5-FU or Cd in mice.