Uno Yasuhiro, Uehara Shotaro, Yamazaki Hiroshi
Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama 642-0017, Japan.
Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
Biochem Pharmacol. 2016 Dec 1;121:1-7. doi: 10.1016/j.bcp.2016.06.008. Epub 2016 Jun 16.
Cynomolgus monkeys (Macaca fascicularis, an Old World Monkey) have been widely used as a non-human primate model in preclinical studies because of their genetic and physiological similarity to humans. This trend has been followed by common marmoset (Callithrix jacchus, a New World Monkey). However, drug-metabolism properties in these non-human primates have not been fully understood due to limited information on cytochrome P450 (P450) enzymes, major drug-metabolizing enzymes in humans. Multiple forms of cynomolgus monkey P450 enzymes have been identified and characterized in comparison to those of humans, including a cynomolgus monkey specific form, P450 2C76. Similarly, marmoset P450 1A/B, 2A, 2C, 2D, and 4F enzymes were recently identified and characterized to understand drug metabolism properties. In this research update, updates for marmoset, cynomolgus monkey, and human P450 cDNAs are provided. Marmoset and cynomolgus monkey P450 enzymes showed high sequence homology to their human counterparts and generally had similar substrate recognition functionality to human P450 enzymes; however, they also possibly contribute to limited specific differences in drug oxidative metabolism partly due to small differences in amino acid residues. These findings provide a foundation for successful use of non-human primates as preclinical models and will help to further understand molecular mechanisms of human P450 function. In addition to the P450 enzymes, flavin-containing monooxygenases, another monooxygenase family, in these non-human primates have been found to be involved in the oxidation of a variety of compounds associated with pharmacological and/or toxicological effects in humans and are also described.
食蟹猴（猕猴属，一种旧世界猴）因其与人类在基因和生理上的相似性，在临床前研究中被广泛用作非人类灵长类动物模型。普通狨猴（绢毛猴属，一种新世界猴）也遵循了这一趋势。然而，由于关于细胞色素P450（P450）酶（人类主要的药物代谢酶）的信息有限，这些非人类灵长类动物的药物代谢特性尚未得到充分了解。与人类的P450酶相比，已鉴定并表征了多种食蟹猴P450酶形式，包括一种食蟹猴特异性形式P450 2C76。同样，最近鉴定并表征了狨猴的P450 1A/B、2A、2C、2D和4F酶，以了解其药物代谢特性。在本研究进展中，提供了狨猴、食蟹猴和人类P450 cDNA的更新信息。狨猴和食蟹猴的P450酶与其人类对应物具有高度的序列同源性，并且通常具有与人类P450酶相似的底物识别功能；然而，它们也可能部分归因于氨基酸残基的微小差异，导致药物氧化代谢存在有限的特定差异。这些发现为成功使用非人类灵长类动物作为临床前模型奠定了基础，并将有助于进一步了解人类P450功能的分子机制。除了P450酶外，还发现这些非人类灵长类动物中的另一个单加氧酶家族——含黄素单加氧酶参与了与人类药理学和/或毒理学效应相关的多种化合物的氧化，本文也对此进行了描述。
