Journal Title
Title of Journal: Arch Toxicol
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Abbravation: Archives of Toxicology
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Publisher
Springer-Verlag
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Authors: Kathrin Eckardt Ralf Stahlmann
Publish Date: 2009/10/25
Volume: 84, Issue: 1, Pages: 37-
Abstract
Mycophenolate mofetil is a widely used immunosuppressive drug that recently has been categorized as a human teratogen Animal experiments indicate a teratogenic potential of the drug but so far it has not been studied in embryotoxicity in vitro assays The aim of this study was to evaluate the in vitro embryotoxic potential of mycophenolic acid and investigate the ability of such tests to detect its embryotoxic potential We used two validated assays the rat whole embryo culture and the murine embryonic stem cell test Rat embryos cultured from gestational day 95 for 48 h with the drug showed dysmorphogenic development already at a concentration of 250 μg mycophenolic acid/l medium At concentrations of 750 μg/l and more all rat embryos exhibited malformations The main effects were defective yolk sac blood circulation neural tube defects open cranial neural pore malformations of the head with missing eye anlagen and heart anomalies Moreover the exposed embryos showed a concentrationdependent decrease in protein content crownrump length number of somites and morphological score The murine embryonic stem cell test was slightly more sensitive Proliferation and differentiation of the ESD3cells were significantly impaired at concentrations of 31 and 125 μg mycophenolic acid/l medium respectively In the differentiation assay at a concentration of 125 μg mycophenolic acid/l medium and more the number of wells with differentiated cardiomyocytes significantly decreased Additionally a cytotoxicity assay with balb/c 3T3 mouse fibroblasts was used to compare the proliferation and vitality of embryonic cells with adult cells In the balb/c 3T3 cytotoxicity assay the number of vital mouse fibroblasts significantly decreased at a mycophenolic acid concentration of 62 μg/l and more In conclusion by using the two validated in vitro tests we showed that mycophenolic acid exhibits a pronounced embryotoxic potential at cytotoxic concentrations This result from validated in vitro tests is of special interest because it supports the use of the tests to detect human teratogens
Keywords:
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- Acknowledgement to referees
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