Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima-city, Kagoshima 890-8580, Japan.
Biochem Pharmacol. 2020 Jan;171:113721. doi: 10.1016/j.bcp.2019.113721. Epub 2019 Nov 18.
The common marmoset (Callithrix jacchus) is a New World monkey that has attracted much attention as a potentially useful primate model for preclinical testing. A total of 36 marmoset cytochrome P450 (P450) isoforms in the P450 1-51 subfamilies have been identified and characterized by the application of genome analysis and molecular functional characterization. In this mini-review, we provide an overview of the genomic structures, sequence identities, and substrate selectivities of marmoset P450s compared with those of human P450s. Based on the sequence identity, phylogeny, and genomic organization of marmoset P450s, orthologous relationships were established between human and marmoset P450s. Twenty-four members of the marmoset P450 1A, 2A, 2B, 2C, 2D, 2E, 3A, 4A, and 4F subfamilies shared high degrees of homology in terms of cDNA (>89%) and amino acid sequences (>85%) with the corresponding human P450s; P450 2C76 was among the exceptions. Phylogenetic analysis using amino acid sequences revealed that marmoset P450s in the P450 1-51 families were located in the same clades as their human and macaque P450 homologs. This finding underlines the evolutionary closeness of marmoset P450s to their human and macaque homologs. Most marmoset P450 1-4 enzymes catalyzed the typical drug-metabolizing reactions of the corresponding human P450 homologs, except for some differences of P450 2A6 and 2B6. Consequently, it appears that the substrate specificities of enzymes in the P450 1-4 families are generally similar in marmosets and humans. The information presented here supports a better understanding of the functional characteristics of marmoset P450s and their similarities and differences with human P450s. It is hoped that this mini-review will facilitate the successful use of marmosets as primate models in drug metabolism and pharmacokinetic studies.
普通狨猴（Callithrix jacchus）是一种新世界猴，作为临床前测试的潜在有用灵长类动物模型，引起了广泛关注。通过基因组分析和分子功能特征分析，共鉴定和表征了 36 种狨猴细胞色素 P450（P450）同工酶，这些同工酶属于 P450 1-51 亚家族。在这个迷你综述中，我们提供了狨猴 P450 与人类 P450 相比的基因组结构、序列同一性和底物选择性的概述。基于狨猴 P450 的序列同一性、系统发育和基因组组织，建立了人类和狨猴 P450 之间的同源关系。狨猴 P450 1A、2A、2B、2C、2D、2E、3A、4A 和 4F 亚家族的 24 个成员在 cDNA（>89%）和氨基酸序列（>85%）方面与相应的人类 P450 高度同源；P450 2C76 是例外之一。使用氨基酸序列进行的系统发育分析表明，P450 1-51 家族中的狨猴 P450 与人类和猕猴 P450 同源物位于同一进化枝中。这一发现强调了狨猴 P450 与其人类和猕猴同源物在进化上的密切关系。除了一些 P450 2A6 和 2B6 的差异外，大多数狨猴 P450 1-4 酶催化了相应的人类 P450 同源物的典型药物代谢反应。因此，似乎 P450 1-4 家族中的酶的底物特异性在狨猴和人类中通常是相似的。这里提供的信息支持了对狨猴 P450 功能特征的更好理解，以及它们与人类 P450 的相似性和差异。希望本迷你综述将有助于成功地将狨猴用作药物代谢和药代动力学研究中的灵长类动物模型。
