Thalidomide teratogenesis: evidence for a toxic arene oxide metabolite.

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Abstract
To determine if thalidomide causes birth defects by being metabolized to a toxic electrophilic intermediate, an in vitro assay was used 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 appears to be an 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 toxic in the system; 2 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 fetuses of rabbit, monkey [Macaca-fascicularis] and human (all sensitive species.) A toxic arene oxide may be involved in the teratogenicity of thalidomide.