CYP2C76 deficiency is embryonic lethal in cynomolgus macaques: The potential role of CYP2C76 in early embryogenesis. Issue 1 (February 2017)

• Record Type: Journal Article
• Authors: Koyama, Shuzo; Fukuda, Koji; Watanabe, Sho; Matsushita, Akinori; Tsuchiya, Hideaki; Fujinami, Nahoko; Kohara, Sakae; Murayama, Norie; Nagano, Masashi; Yamazaki, Hiroshi; Fukuzaki, Koichiro; Uno, Yasuhiro; Hosoi, Yoshihiko
• Is Part Of: Drug metabolism and pharmacokinetics. Volume 32:Issue 1(2017)
• Page Start: 112
• Page End: 115
• Publication Date: 2017-02
• Subjects: Cytochrome P450 -- Embryogenesis -- Progesterone -- Null allele -- Cynomolgus macaque; ART assisted reproduction technology -- P450 cytochrome P450 (EC 1.14.14.1) -- ICSI intracytoplasmic sperm injection -- PCR polymerase chain reaction -- PGD preimplantation genetic diagnosis -- RT reverse transcription; Drugs -- Metabolism -- Periodicals; Pharmacokinetics -- Periodicals; 615.7
• DOI: 10.1016/j.dmpk.2016.10.411
• Languages: English
• ISSNs: 1347-4367

Abstract

Abstract: Cynomolgus macaques are an important primate species for drug metabolism studies; however cynomolgus CYP2C76, an important drug-metabolizing enzyme, accounts for drug metabolism differences to humans, so that CYP2C76-null animals might show drug-metabolizing properties more similar to humans. In this study, attempts were made to produce CYP2C76-null animals by assisted reproduction technology. Oocytes and sperm collected from the heterozygotes for the null allele (c.449TG > A) were subjected to intracytoplasmic sperm injection, and the embryos produced were cultured in vitro through the blastocyst stage. Preimplantation genetic diagnosis using a biopsied portion of the blastocyst revealed that none of the 32 blastocysts analyzed were homozygotes. In contrast, 2 of the 20 embryos analyzed were homozygotes at the 8-cell stage, indicating that CYP2C76-null embryos most likely stop developing between the 8-cell and blastocyst stage. By polymerase chain reaction, expression of CYP2C76 mRNA was detected in oocytes and blastocysts, but not in 2-, 4-, 8-, or 16/32-cell stage embryos. Metabolic assays showed that CYP2C76 metabolized progesterone. These results indicated that CYP2C76 null was likely embryonic lethal, suggesting its potential role during early embryogenesis in cynomolgus macaques.