Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University , 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University , 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
Mol Pharm. 2018 Jan 2;15(1):127-140. doi: 10.1021/acs.molpharmaceut.7b00772. Epub 2017 Dec 5.
Cynomolgus monkeys have been widely used for the prediction of drug absorption in humans. The purpose of this study was to clarify the regional protein expression levels of cytochromes P450 (CYPs), UDP-glucuronosyltransferases (UGTs), and transporters in small intestine of cynomolgus monkey using liquid chromatography-tandem mass spectrometry, and to compare them with the corresponding levels in human. UGT1A1 in jejunum and ileum were >4.57- and >3.11-fold and UGT1A6 in jejunum and ileum were >16.1- and >8.57-fold, respectively, more highly expressed in monkey than in human. Also, jejunal expression of monkey CYP3A8 (homologue of human CYP3A4) was >3.34-fold higher than that of human CYP3A4. Among apical drug efflux transporters, BCRP showed the most abundant expression in monkey and human, and the expression levels of BCRP in monkey and human were >1.74- and >1.25-fold greater than those of P-gp and >2.76- and >4.50-fold greater than those of MRP2, respectively. These findings should be helpful to understand species differences of the functions of CYPs, UGTs, and transporters between monkey and human. The UGT1A1/1A6 data would be especially important because it is difficult to identify isoforms responsible for species differences of intestinal glucuronidation by means of functional studies due to overlapping substrate specificity.
食蟹猴被广泛用于预测人体对药物的吸收。本研究旨在使用液质联用技术阐明食蟹猴小肠细胞色素 P450（CYP）、UDP-葡糖醛酸基转移酶（UGT）和转运体的区域性蛋白表达水平，并将其与人类相应水平进行比较。空肠和回肠的 UGT1A1 在猴体内的表达水平分别是人体内的 4.57 倍和 3.11 倍，空肠和回肠的 UGT1A6 表达水平分别是人体内的 16.1 倍和 8.57 倍；猴 CYP3A8（人 CYP3A4 的同源物）在空肠中的表达水平比人 CYP3A4 高 3.34 倍。在顶端药物外排转运体中，BCRP 在猴和人体内的表达最为丰富，猴和人体内 BCRP 的表达水平分别比 P-gp 高 1.74 倍和 1.25 倍，比 MRP2 高 2.76 倍和 4.50 倍。这些发现有助于了解猴和人体内 CYP、UGT 和转运体功能的种属差异。由于在功能研究中由于底物特异性重叠，难以通过鉴定负责肠内葡萄糖醛酸化的同工酶来识别种属差异，因此 UGT1A1/1A6 的数据尤为重要。
