Thalidomide and Congenital Abnormalities

Speirs, A. L.

doi:10.1016/s0140-6736(62)91248-5

Cited by 159 publications

(64 citation statements)

References 3 publications

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“…Thalidomide was identified as a human teratogen 20 years ago (1)(2)(3). Compared to other teratogens, thalidomide's selective toxicity in the embryo, particularly for the developing limbs, and its relative lack oftoxicity in the adult is striking (4).…”

mentioning

confidence: 99%

Thalidomide teratogenesis: evidence for a toxic arene oxide metabolite.

Gordon¹,

Spielberg²,

Blake³

et al. 1981

Proc. Natl. Acad. Sci. U.S.A.

145

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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 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 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.Thalidomide was identified as a human teratogen 20 years ago (1-3). Compared to other teratogens, thalidomide's selective toxicity in the embryo, particularly for the developing limbs, and its relative lack oftoxicity in the adult is striking (4). Despite intensive investigation, however, the mechanism of the fetal toxicity of the drug remains unknown.An interesting early observation was that rats were resistant to the teratogenic effects of thalidomide but rabbits and monkeys were sensitive (5-7). Differences in species susceptibility could result from differences in biotransformation of the compound. It was noted that rabbit liver homogenates enhanced the rate of disappearance of the drug from incubation mixtures whereas rat liver homogenates did not (8). Similarly, in vivo, more thalidomide metabolites were bound to liver macromolecules in the rabbit than in the rat, suggesting that a metabolite might interact covalently with macromolecules important in morphogenesis. Furthermore, after thalidomide treatment, 4-and 5-hydroxylated metabolites of thalidomide were recovered from the urine of rabbits but not from rats (9).The presence ofphenolic derivatives ofthalidomide suggests that the drug might undergo oxidative metabolism via an arene oxide intermediate. Arene oxides have been implicated as mutagens, cytotoxins, and teratogens (10-12). Thus, birth defects caused by the anticonvulsant phenytoin may result from an arene oxide metabolite which covalently binds to critical structures in the developing fetus (12). Therefore, we have attempted to look for a possible toxic arene oxide metabolite ofthalidomide. We have used an in vitro assay system in which human lymphocytes are the target of metabol...

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mentioning

confidence: 99%

Thalidomide teratogenesis: evidence for a toxic arene oxide metabolite.

Gordon¹,

Spielberg²,

Blake³

et al. 1981

Proc. Natl. Acad. Sci. U.S.A.

145

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“…2,3, [6][7][8][9][10][11][12][13][14] Deficiency or malformation affected four limbs in 10 (37%) of the patients reviewed, three limbs in seven patients (26%), two limbs in another seven patients (26%) and one limb only in three patients (11%). The major skeletal defects (Table 1) were hypoplasia or aplasia, mainly of the long bones, the femur being predominantly affected.…”

Section: Resultsmentioning

confidence: 99%

Thalidomide-induced limb malformations — a prosthetic review

Mustapha

1990

Clin Rehabil

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The embryopathy-producing drug 'thalidomide' resulted in an estimated 349 babies born in the UKwith congenital malformations during the period 1959-62. All known affected babies were registered, and a 'Thalidomide Society and Trust' was formed to administer the financial settlements offered by the manufacturers of the drug and the British Government. Individual prosthetic centres found great difficulty at the time in dealing with the complicated malformations these children presented, and it was found necessary to set up four specialized centres to develop new prosthetic/orthotic designs and fitting techniques. It was possible to review only 27 adults, as the majority were lost to follow-up. Those reviewed were all well adjusted (even those who had four limb malformations) and relatively independent. Their range of lifestyles is comparable with their nondisabled peers. The financial awards, proper home adaptations and adequate provision of aids to mobility and activities of daily living all contributed significantly to an enhanced quality of life. A peripatetic team, in consultation with the patients and the local team, offered suggestions and improvements in both prosthetic aids (making use of recent developments) and other aids to mobility and activities of daily living. The results of the study highlight the need for such a peripatetic team of experts to periodically review the prosthetic needs of complex multiple limb handicap. 194

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“…The appendix was absent in 4 of the 10 autopsies on thalidomide babies which have been reported (Ucutier, 1962;Ling et al, 1962;Spiers, 1962;Stewart, 1963).…”

Section: Discussionmentioning

confidence: 96%