Mycophenolic Acid-Induced Developmental Defects in Zebrafish Embryos. (November 2016)

• Record Type: Journal Article
• Authors: Jiang, Ling-Ling; Liu, Mei-Hui; Li, Jian-Ying; He, Zhi-Heng; Li, Huan; Shen, Ning; Wei, Ping; He, Ming-Fang
• Is Part Of: International journal of toxicology. Volume 35:Number 6(2016)
• Page Start: 712
• Page End: 718
• Publication Date: 2016-11
• Subjects: mycophenolic acid -- inosine monophosphate dehydrogenase -- zebrafish embryos -- developmental toxicity; Toxicology -- Periodicals; 615.9005
• DOI: 10.1177/1091581816668308
• Languages: English
• ISSNs: 1091-5818

Abstract

With the increasing use of mycophenolic acid (MPA) in solid organ transplantation, some clinical studies indicate that it is also a human teratogen. However, it is unknown by which mechanism MPA acts as a teratogen. Mycophenolic acid was a selective blocker of de novo purine synthesis, and its immunosuppressive effect is mediated by the inhibition of inosine monophosphate dehydrogenase, which could be a target for MPA-induced toxicity as well. The aim of our study was to examine the direct influence of MPA exposure on zebrafish ( Danio rerio ) embryos. Morphological defects including tail curvature and severe pericardial edema in zebrafish embryos caused by MPA (3.7-11.1 µmol/L) were found in a dose-dependent manner. The teratogenic index (25% lethal concentration value (LC25 )/no observed adverse effect level ratio) was 16, which indicated MPA as a teratogen. Quantitative polymerase chain reaction analysis revealed that the expression level of impdh1b and impdh2 was significantly reduced by MPA treatment at 8 µmol/L (equals to LC25 level). All the toxic effects could be partially reversed by the addition of 33.3 µmol/L guanosine. Our results indicated that MPA impairs the development of zebrafish embryos via inhibition of impdh activity, which subsequently caused a guanosine nucleotide depletion in vivo.