TERATOGENIC EFFECTS OF THALIDOMIDE AND ITS METABOLITES ON THE DEVELOPING CHICK EMBRYO

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Abstract
The teratogenicity of α-N-phthalimidoglutarimide (thalidomide) and related substances was studied in the developing chick embryo. Whereas doses of thalidomide up to 10 mg had little or no effect on the 4-day-old embryo, 0.5 mg injected into the yolk sac just prior to incubation produced micromelia and edema, which were rarely seen in the controls. Other abnormalities observed were rumplessness, cerebral hernia, and defects of the eyes and beak, which were also present, but to a lesser extent, in the controls.Metabolites of thalidomide which are found in the urine of rabbits after oral administration of this drug were also investigated. α-N-Phthaloylglutamine and α-N-phthaloylglutamic acid had little effect, suggesting that hydrolytic cleavage of the glutarimide ring of thalidomide results in decreased teratogenicity. However, increased teratogenicity was shown by hydroxylated derivatives of these compounds and of thalidomide in which the hydroxyl group was located in the 3- or 4-position of the phthalimido group, the 4-hydroxylated derivatives being the more effective.It was found that 4.0 mg of L-glutamine, injected simultaneously with 2.0 mg of α-N-(4-hydroxyphthaloyl)-glutamine, gave complete protection against micromelia and edema and reduced the incidence of other abnormalities almost to the control level. No protection was given by L-glutamic acid, pyridoxal hydrochloride, pteroyl-L-glutamic acid, citrovorum factor, nicotinamide, or quinolinic acid. These results suggest that α-N-(4-hydroxyphthaloyl)-glutamine and probably its congeners may interfere with the metabolism of glutamine.