Teratogenic Effects of Thalidomide in Rabbits, Rats, Hamsters and Mice

Fratta, Italo; Sigg, E.B.; Maiorana, K.; Davies, Sara

doi:10.3109/13590849009003163

Cited by 30 publications

(45 citation statements)

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“…We do not know whether the thalidomide metabolites detected in the embryo fibroblast assay system can also cause thalidomide-induced teratogenesis and/or anti-angiogenesis. However, the present results in the system of embryo fibroblasts were consistent with reported species differences in thalidomideinduced teratogenesis (Delahunt et al, 1965;Fratta et al, 1965;Schumacher et al, 1968) and anti-angiogenesis (Bauer et al, 1998).…”

Section: Discussionsupporting

confidence: 82%

“…Rabbits and humans are known to be susceptible to the teratogenic effect of thalidomide, while rodents were resistant (Delahunt et al, 1965;Fratta et al, 1965;Schumacher et al, 1968). No significant decrease was found in cell numbers of mouse embryo fibroblasts after contact with supernatants of mouse liver microsomes preincubated with 30 or 100 M thalidomide (Fig.…”

Section: Effect Of Thalidomide Metabolites On Cell Number Of Rabbitmentioning

confidence: 99%

“…Rodents were resistant to the teratogenic effects of thalidomide, but rabbits, monkeys and humans were susceptible (Delahunt et al, 1965;Fratta et al, 1965;Schumacher et al, 1968). Parman et al (1999) reported that thalidomide enhanced embryonic DNA oxidation in rabbits but not in mice even at a three times higher dose than that used in rabbits.…”

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confidence: 99%

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Thalidomide-induced Suppression of Embryo Fibroblast Proliferation Requires CYP1A1-Mediated Activation

Miyata

Tamura²,

Motoki³

et al. 2003

Drug Metabolism and Disposition

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:An enzyme involved in the metabolic activation of thalidomide has been investigated using embryo fibroblast proliferation as a marker. Thalidomide (30 M) induced-suppression of embryo fibroblast proliferation was detected in the presence of liver microsomes from rabbit but not from mouse. The addition of a selective inhibitor of CYP1A, ␣-naphthoflavone (4 M), or furafylline (4 M), to the incubation mixture abolished the thalidomide-induced suppression. Furthermore, addition of anti-rat CYP1A1 antibody also resulted in inhibition of suppression. The thalidomide-induced suppression was also observed with the microsomal system from human HepG2 cells pretreated with 3-methylcholanthrene (10 M) but not from those pretreated with the vehicle. Both CYP1A1 and CYP1A2 proteins were detected in the rabbit liver microsomes by immunoblot analyses, but only CYP1A2 protein was detected in the mouse liver microsomes. In addition, CYP1A1 protein was detected in microsomes from HepG2 cells pretreated with 3-methylcholanthrene but not with the vehicle. These results strongly suggest the involvement of CYP1A1 in the thalidomide-induced suppression of embryo fibroblast proliferation.

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Section: Discussionsupporting

confidence: 82%

Section: Effect Of Thalidomide Metabolites On Cell Number Of Rabbitmentioning

confidence: 99%

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Thalidomide-induced Suppression of Embryo Fibroblast Proliferation Requires CYP1A1-Mediated Activation

Miyata

Tamura²,

Motoki³

et al. 2003

Drug Metabolism and Disposition

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“…The adverse effects of thalidomide have been shown to be caused by the inhibition of cereblon, a component of the ubiquitin ligase that is important for the expression of an essential regulator of limb development. However, zebra fish and chickens were used in this study because the adverse effects of thalidomide are difficult to detect in rodents (4,5,14). For these reasons, the in vitro developmental toxicity test based on hiPSCs would be a useful tool to assess the developmental toxicity of candidate drugs in humans.…”

Section: Discussionmentioning

confidence: 99%

“…However, the adverse effects of thalidomide are difficult to detect in in vivo reproductive and developmental studies in rodents (4,5). This may be due to species barrier-related differences between rodents and humans.…”

Section: Introductionmentioning

confidence: 99%

Detection of Thalidomide Embryotoxicity by In Vitro Embryotoxicity Testing Based on Human iPS Cells

et al. 2014

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Abstract. The mouse embryonic stem cell test (mEST) is used to assess the embryotoxicity of drug candidates by evaluating the effects on the cardiac differentiation of stem cells. However, thalidomide embryotoxicity has not yet been reported using the mEST. To detect the effects of thalidomide, we used human induced pluripotent stem cells (hiPSCs) instead of mouse embryonic stem cells, and assessed three endpoints: the inhibition of cardiac differentiation, the cytotoxicity to hiPSCs, and the cytotoxicity to human dermal fibroblasts, according to the mEST. From these data (IC 50 values), the embryotoxicity was classified into one of three different classes based on the mEST and our criteria. Valproate was used as a positive control and ascorbic acid was used as a negative control, and their effects were assessed. Similar to valproate, thalidomide was classified as a Class 2 agent, with weak embryotoxicity, by the mEST criteria, and was classified as Category 3 embryotoxic based on our criteria. Ascorbic acid was classified as a Class 1 / Category 1, non-embryotoxic agent, based on both criteria. Thalidomide embryotoxicity was detected in the embryonic stem cell test based on hiPSCs. This test system is thus considered to have a much greater predictive ability than the mEST.

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Evaluation of the developmental toxicity of thalidomide using frog embryo teratogenesis assay?Xenopus (FETAX): biotransformation and detoxification

Fort

Stover²,

Bantle

et al. 2000

Teratogenesis Carcinog. Mutagen.

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Teratogenic Effects of Thalidomide in Rabbits, Rats, Hamsters and Mice

Cited by 30 publications

References 0 publications

Thalidomide-induced Suppression of Embryo Fibroblast Proliferation Requires CYP1A1-Mediated Activation

Thalidomide-induced Suppression of Embryo Fibroblast Proliferation Requires CYP1A1-Mediated Activation

Detection of Thalidomide Embryotoxicity by In Vitro Embryotoxicity Testing Based on Human iPS Cells

Evaluation of the developmental toxicity of thalidomide using frog embryo teratogenesis assay?Xenopus (FETAX): biotransformation and detoxification

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