Pharmacological properties and teratogenic action of 2-[Hexahydrophthalimido] glutarimide and 2-phthalimido-N-methylglutarimide

Wuest, H; Sigg, E.B.; Fratta, Italo

doi:10.1016/0024-3205(64)90025-6

Cited by 18 publications

(4 citation statements)

References 3 publications

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“…Purified epoxide hydrolase protected against toxicity caused by the analogs (data not shown). In contrast, two nonteratogenic analogs, phthalimide (20,21) and hexahydrothalidomide (20, 21), did not cause toxicity in the presence or absence of TCPO. In the case of hexahydrothalidomide, there was no toxicity at concentrations 80 times the minimal thalidomide concentration associated with toxicity in the system.…”

mentioning

confidence: 83%

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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confidence: 83%

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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“…Studies in the early 1960s postulated and investigated the possibility that the rapidly formed hydrolysis products of TD might contribute to teratogenesis. However, these studies were limited to the use of in vivo models available at the time, with inconclusive and contradictory results (36,(53)(54)(55)(56)(57)(58). More recently, the developmental effects of TD have been studied in a number of in vitro models, including cell and limb bud cell culture and zebrafish embryo culture (9,18,20,31,59), as well as in vivo animal models, including rabbits, primates, and chicks (12,13,15,19,60) to gain insights into its teratogenic mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Embryopathic effects of thalidomide and its hydrolysis products in rabbit embryo culture: evidence for a prostaglandin H synthase (PHS)‐dependent, reactive oxygen species (ROS)‐mediated mechanism

2011

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Thalidomide (TD) causes birth defects in humans and rabbits via several potential mechanisms, including bioactivation by embryonic prostaglandin H synthase (PHS) enzymes to a reactive intermediate that enhances reactive oxygen species (ROS) formation. We show herein that TD in rabbit embryo culture produces relevant embryopathies, including decreases in head/brain development by 28% and limb bud growth by 71% (P<0.05). Two TD hydrolysis products, 2-phthalimidoglutaramic acid (PGMA) and 2-phthalimidoglutaric acid (PGA), were similarly embryopathic, attenuating otic vesicle (ear) and limb bud formation by up to 36 and 77%, respectively (P<0.05). TD, PGMA, and PGA all increased embryonic DNA oxidation measured as 8-oxoguanine (8-oxoG) by up to 2-fold (P<0.05). Co- or pretreatment with the PHS inhibitors eicosatetraynoic acid (ETYA) or acetylsalicylic acid (ASA), or the free-radical spin trap phenylbutylnitrone (PBN), completely blocked embryonic 8-oxoG formation and/or embryopathies initiated by TD, PGMA, and PGA. This is the first demonstration of limb bud embryopathies initiated by TD, as well as its hydrolysis products, in a mammalian embryo culture model of a species susceptible to TD in vivo, indicating that all likely contribute to TD teratogenicity in vivo, in part through PHS-dependent, ROS-mediated mechanisms.

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“…Table 1 shows the structures of some 12 compounds including thalidomide itself which have been shown beyond reasonable doubt to have teratogenic properties in pregnant rabbits and/or monkey species. 23,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] It should be noted that the actual number is 8 compounds because 4 of these are enantiomers. Thalidomide and its structural analogue EM12 both carry an asymmetric chiral centre and all three forms (DL, D, L) have been shown to be teratogenic.…”

Section: Embryopathic Effectsmentioning

confidence: 99%

“…46 Table 4 indicates 8 structural analogues of thalidomide (compounds 25-32) in which the phthalimide ring has been replaced by various alternative ring structures such as benzothiazole (compounds 25-27) or succinimido (compound 32) all of which proved to be inactive as teratogens in the pregnant rabbit. 33,34,36,37,[46][47][48][49] Thalidomide analogue EM12 S-(−)-enantiomer [9] (3S)-3-(1-Oxo-1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione Marmoset 39,41 Thalidomide analogue EM12 R-(+)-enantiomer [10] (3R)-3-(1-Oxo-1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione Marmoset 39,41 Thalidomide analogue EM136 [11] 3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2yl) piperidine-2-one…”

Section: Embryopathic Effectsmentioning

confidence: 99%