Comparative Biochemistry and Physiology C: Toxicology & Pharmacology ( IF 3.9 ) Pub Date : 2022-12-20 , DOI: 10.1016/j.cbpc.2022.109534 Yasuhiro Uno 1 , Yutaro Noda 2 , Norie Murayama 2 , Kyoko Tsukiyama-Kohara 1 , Hiroshi Yamazaki 2
Tree shrews (Tupaia belangeri) are a non-rodent primate-like species sometimes used for biomedical research involving hepatitis virus infections and toxicology. Genome analysis has indicated similarities between tree shrews and humans in the numbers of cytochromes P450 (P450 or CYP), which constitute a family of important drug-metabolizing enzymes; however, P450s have not been fully investigated in tree shrews. In this study, we identified CYP1A1, CYP1A2, CYP1B1, and CYP1D1 cDNAs from tree shrew liver and compared their characteristics with dog, pig, and human CYP1As. The deduced amino acid sequences of tree shrew CYP1s were highly identical (82–87 %) to human CYP1s. In tree shrews, CYP1A1 and CYP1A2 mRNAs were preferentially expressed in liver, whereas CYP1D1 mRNA was preferentially expressed in kidney and lung. In contrast, CYP1B1 mRNA was expressed in various tissues, with the most abundant expression in spleen. Among the tree shrew CYP1 mRNAs, CYP1A2 mRNA was most abundant in liver, and CYP1B1 mRNA was most abundant in kidney, small intestine, and lung. All tree shrew CYP1 proteins heterologously expressed in Escherichia coli catalyzed caffeine and estradiol in a similar manner to tree shrew liver microsomes and human, dog, and pig CYP1 proteins. These results suggest that tree shrew CYP1A1, CYP1A2, CYP1B1, and CYP1D1 genes, different form human pseudogene CYP1D1P, are expressed in liver, small intestine, lung, and/or kidney and encode functional drug-metabolizing enzymes important in toxicology.
中文翻译:
树鼩中新型细胞色素 P450 1 (CYP1) 基因的表达和编码功能性药物代谢酶
树鼩 ( Tupaia belangeri) 是一种非啮齿类灵长类动物,有时用于涉及肝炎病毒感染和毒理学的生物医学研究。基因组分析表明,树鼩和人类在细胞色素 P450(P450 或 CYP)的数量上存在相似之处,这些细胞色素构成了一个重要的药物代谢酶家族;然而,P450 尚未在树鼩中得到充分研究。在这项研究中,我们鉴定了树鼩肝脏中的 CYP1A1、CYP1A2、CYP1B1 和 CYP1D1 cDNA,并将它们的特性与狗、猪和人类的 CYP1A 进行了比较。推导的树鼩 CYP1 氨基酸序列与人类 CYP1 高度一致 (82–87%)。在树鼩中,CYP1A1 和 CYP1A2 mRNA 优先在肝脏中表达,而 CYP1D1 mRNA 优先在肾脏和肺中表达。相反,CYP1B1 mRNA 在各种组织中表达,在脾脏中表达最丰富。在树鼩CYP1 mRNA中,CYP1A2 mRNA在肝脏中含量最高,CYP1B1 mRNA在肾脏、小肠和肺中含量最高。所有树鼩 CYP1 蛋白异源表达于大肠杆菌以类似于树鼩肝微粒体和人类、狗和猪 CYP1 蛋白的方式催化咖啡因和雌二醇。这些结果表明,树鼩CYP1A1、CYP1A2、CYP1B1和CYP1D1基因与人类假基因CYP1D1P不同,在肝脏、小肠、肺和/或肾脏中表达,并编码毒理学中重要的功能性药物代谢酶。