Automated in Vitro Screening of Teratogens

Walmod, Peter S.; Berezin, Anton; Gallagher, Helen C.; Gravemann, Ute; Lepekhin, Eugene A.; Belman, Vadym; Bacon, Christopher L.; Nau, Heinz; Regan, Ciaran M.; Berezin, Vladimir; Bock, Elisabeth

doi:10.1006/taap.2002.9393

Cited by 21 publications

(22 citation statements)

References 44 publications

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“…Recently, effects of thalidomide on cytotoxicity and proliferation were evaluated using mouse fibroblastoid L929 cells resulting in no significant effect of thalidomide on cytotoxicity and proliferation (Walmod et al, 2002). These results are consistent with our experimental data on the direct treatment of embryo fibroblast with thalidomide (Miyata et al, 2002b).…”

Section: Discussionsupporting

confidence: 89%

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

Miyata

Tamura²,

Motoki³

et al. 2003

Drug Metab Dispos

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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: 89%

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

Miyata

Tamura²,

Motoki³

et al. 2003

Drug Metab Dispos

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“…In mouse models, pentyl‐4‐yn‐VPA is a stronger teratogen than VPA and the same rank order of potency applies to the anti‐proliferative/pro‐differentiative action of these agents in various cell lines of diverse origin (Bojic et al . 1998; Walmod et al . 2002).…”

Section: Discussionmentioning

confidence: 99%

Differential enantioselective effects of pentyl‐4‐yn‐valproate on spatial learning in the rat, and neurite outgrowth and cyclin D3 expression in vitro

O'Loinsigh

Gherardini

Gallagher

et al. 2003

Journal of Neurochemistry

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Previously, we demonstrated the racemic form of the valproate (VPA) analogue, 2-n-pentyl-4-pentynoic acid ([±]pentyl-4-yn-VPA), to be neuritogenic in vitro and to enhance cognition in vivo. To determine the enantioselectivity of these effects, the racemate and purified enantiomers of [±]pentyl-4-yn-VPA (84 mg/kg, i.p.) were administered to rodents 20 min prior to multi-session water maze training. The racemate and R-enantiomer significantly reduced escape latencies during water maze learning and enhanced its recall in a probe trial 3 days later. In contrast, S-pentyl-4-yn-VPA did not influence these behavioural parameters. The enantiomerspecific effects of [±]pentyl-4-yn-VPA were further discriminated in vitro using neuro 2A neuroblastoma and C6 glioma cell lines. In neuro 2A, the S-enantiomer induced profound neurite outgrowth at concentrations up to 0.5 mM, with the R-enantiomer and racemate being less neuritogenic. Immunoblot analysis of cyclin D3 expression in C6 glioma indicated the racemate and S-pentyl-4-yn-VPA to induce dosedependent up-regulation of this protein, similar to that associated with G1-phase cell cycle arrest mediated by VPA, whereas R-pentyl-4-yn-VPA was without effect. These results indicate that the cognition-enhancing effects of pentyl-4-yn-VPA are due to the actions of the R-enantiomer, and that cyclin D3 up-regulation and associated anti-proliferative and pro-differentiative actions are predominantly associated with the S-enantiomer.

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“…In a new in vivo assay for screening of potential teratogens based on stemming cultured mouse fibroblastoid L929 cells, VA demonstrated teratogenic properties in vivo. It caused alterations in cell morphology and proliferation [12] . VA treatment induced apoptotic changes in MV411 cells, including DNA frag- mentation, phosphatidylserine externalization, cytochrome c release from mitochondria, and activation of caspases 3, 8 and 9 [13] .…”

Section: Discussionmentioning

confidence: 99%

Cytogenetic Effects of Valproic Acid and Ziprasidone in Human Lymphocyte Cultures

Karapidaki

Ekonomopoulou²,

Akritopoulou³

et al. 2011

Neuropsychobiology

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Background/Aims: Valproic acid or valproate (VA) is an anticonvulsant and mood-stabilizing drug primarily used in the treatment of epilepsy and bipolar disorder. Ziprasidone (ZPN) is an atypical antipsychotic drug used mainly for the treatment of schizophrenia. Methods: This study is a part of our investigation on the cytogenetic effects of psychotropic drugs. Lymphocytes of peripheral blood cultures from 3 healthy donors treated with VA, ZPN and combinations of these (at concentrations equivalent to the oral doses) were used for the estimation of sister chromatid exchanges (SCEs) and the proliferation rate index (PRI). As a biomarker of genotoxicity, we used SCEs, one of the most sensitive methods reflecting DNA damage and/or subsequent DNA repair, and as a marker of cytostaticity we estimated the PRI. Results: All treated lymphocyte cultures showed a statistically significant increase in SCE frequency and a significant decrease in PRI values (p < 0.001). The combined effect of the drugs induced similar or more intense results, without reaching levels indicating synergistic action. Conclusion: This in vitro study investigated the cytogenetic activity of monotherapy vs. combined chronic drug exposure, and could form a catalyst for further investigations aiming to develop more efficacious therapy with decreased cytogenetic damage.

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Automated in Vitro Screening of Teratogens

Cited by 21 publications

References 44 publications

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

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

Differential enantioselective effects of pentyl‐4‐yn‐valproate on spatial learning in the rat, and neurite outgrowth and cyclin D3 expression in vitro

Cytogenetic Effects of Valproic Acid and Ziprasidone in Human Lymphocyte Cultures

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