Mycophenolic Acid-Induced Developmental Defects in Zebrafish Embryos.
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 LC25level). 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.
Institute of Translational Medicine, College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, People's Republic of China.
Ling-Ling
LL
Jiang
Department of Pharmaceutical Sciences, Jiangsu Jiankang Vocational College, Nanjing, People's Republic of China.
Mei-Hui
MH
Liu
Nanjing Emory Biotechnology Company, Nanjing, People's Republic of China.
Jian-Ying
JY
Li
School of Medicine, Yale University, New Haven, CT, USA.
Zhi-Heng
ZH
He
Institute of Translational Medicine, College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, People's Republic of China.
Huan
H
Li
Institute of Translational Medicine, College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, People's Republic of China.
Ning
N
Shen
Institute of Translational Medicine, College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, People's Republic of China.
Ping
P
Wei
Institute of Translational Medicine, College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, People's Republic of China mingfanghe@hotmail.com.
Ming-Fang
MF
He
D000818:Animals; D004625:Embryo, Nonmammalian; D047108:Embryonic Development / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006151:Guanosine / Q000494:pharmacology; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007928:Lethal Dose 50; D009173:Mycophenolic Acid / Q000633:toxicity*; D019055:No-Observed-Adverse-Effect Level; D013623:Tail / Q000002:abnormalities; D013723:Teratogens / Q000633:toxicity*; D015027:Zebrafish
D007166:Immunosuppressive Agents; D013723:Teratogens; D006151:Guanosine; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid
developmental toxicity; inosine monophosphate dehydrogenase; mycophenolic acid; zebrafish embryos