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Mycophenolic Acid-Induced Developmental Defects in Zebrafish Embryos.
Int J Toxicol. 2016 11; 35(6):712-718.IJ

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.

Authors+Show Affiliations

Institute of Translational Medicine, College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, People's Republic of China.Department of Pharmaceutical Sciences, Jiangsu Jiankang Vocational College, Nanjing, People's Republic of China.Nanjing Emory Biotechnology Company, Nanjing, People's Republic of China.School of Medicine, Yale University, New Haven, CT, USA.Institute of Translational Medicine, College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, People's Republic of China.Institute of Translational Medicine, College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, People's Republic of China.Institute of Translational Medicine, College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, People's Republic of China.Institute of Translational Medicine, College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, People's Republic of China mingfanghe@hotmail.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27694306

Citation

Jiang, Ling-Ling, et al. "Mycophenolic Acid-Induced Developmental Defects in Zebrafish Embryos." International Journal of Toxicology, vol. 35, no. 6, 2016, pp. 712-718.
Jiang LL, Liu MH, Li JY, et al. Mycophenolic Acid-Induced Developmental Defects in Zebrafish Embryos. Int J Toxicol. 2016;35(6):712-718.
Jiang, L. L., Liu, M. H., Li, J. Y., He, Z. H., Li, H., Shen, N., Wei, P., & He, M. F. (2016). Mycophenolic Acid-Induced Developmental Defects in Zebrafish Embryos. International Journal of Toxicology, 35(6), 712-718.
Jiang LL, et al. Mycophenolic Acid-Induced Developmental Defects in Zebrafish Embryos. Int J Toxicol. 2016;35(6):712-718. PubMed PMID: 27694306.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mycophenolic Acid-Induced Developmental Defects in Zebrafish Embryos. AU - Jiang,Ling-Ling, AU - Liu,Mei-Hui, AU - Li,Jian-Ying, AU - He,Zhi-Heng, AU - Li,Huan, AU - Shen,Ning, AU - Wei,Ping, AU - He,Ming-Fang, Y1 - 2016/09/30/ PY - 2016/10/4/pubmed PY - 2018/1/23/medline PY - 2016/10/4/entrez KW - developmental toxicity KW - inosine monophosphate dehydrogenase KW - mycophenolic acid KW - zebrafish embryos SP - 712 EP - 718 JF - International journal of toxicology JO - Int. J. Toxicol. VL - 35 IS - 6 N2 - 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. SN - 1092-874X UR - https://www.unboundmedicine.com/medline/citation/27694306/Mycophenolic_Acid_Induced_Developmental_Defects_in_Zebrafish_Embryos_ L2 - http://journals.sagepub.com/doi/full/10.1177/1091581816668308?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -