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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1981 Apr;78(4):2545–2548. doi: 10.1073/pnas.78.4.2545

Thalidomide teratogenesis: evidence for a toxic arene oxide metabolite.

G B Gordon, S P Spielberg, D A Blake, V Balasubramanian
PMCID: PMC319385  PMID: 6941308

Abstract

It was postulated that thalidomide causes birth defects by being metabolized to a toxic electrophilic intermediate. This hypothesis was tested by using an in vitro assay in which drug toxicity to human lymphocytes was assessed in the presence of a hepatic microsomal drug metabolizing system. Maternal hepatic microsomes from pregnant rabbits mediated the production of a metabolite that was toxic to lymphocytes. Toxicity was enhanced by inhibitors of epoxide hydrolase (EC 3.3.2.3) and abolished by adding the purified enzyme to the incubation medium. The metabolite thus appears to be in arene oxide, consistent with the previously reported isolation of phenolic metabolites of thalidomide from the urine of treated animals. Two teratogenic analogs of thalidomide (phthalimidophthalimide and phthalimidinoglutarimide) were also toxic in the system; two nonteratogenic analogs (phthalimide and hexahydrothalidomide) were not toxic, even in the presence of epoxide hydrolase inhibitors. The toxic metabolite of thalidomide was not produced by rat liver microsomes (the rat is not sensitive to thalidomide teratogenesis) but was produced by hepatic preparations from maternal rabbits, and rabbit, monkey, and human (all sensitive species) fetuses. A toxic arene oxide therefore may be involved in the teratogenicity of thalidomide.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

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