Uehara Shotaro, Murayama Norie, Yamazaki Hiroshi, Uno Yasuhiro
Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan.
Xenobiotica. 2010 Sep;40(9):621-9. doi: 10.3109/00498254.2010.501118.
A novel cytochrome P450 (CYP), CYP2A26, was identified and characterized in cynomolgus monkey, one of the animal species used in preclinical studies. Deduced amino acid sequences of CYP2A26 cDNA showed high sequence identities (91–95%) with cynomolgus monkey CYP2A23 and CYP2A24, and human CYP2A6 and CYP2A13. Phylogenetic analysis showed that macaque CYP2As (CYP2A26, CYP2A23, and CYP2A24) were most closely clustered with human CYP2As, unlike CYP2As of dog, rat, and mouse (other species also used in drug metabolism). Quantitative polymerase chain reaction analysis showed that CYP2A26 mRNA, along with CYP2A23 and CYP2A24 mRNAs, was expressed predominantly in the liver, where CYP2A proteins were also detected by immunoblotting. Drug-metabolizing assays using the CYP2A26 protein heterologously expressed in Escherichia coli indicated that CYP2A26 catalyzed coumarin 7-hydroxylation with its apparent K(m) lower than that of CYP2A24, but similar to those of CYP2A6 and CYP2A23. These results suggest an evolutionary closeness and functional similarity of cynomolgus monkey CYP2A26 (together with CYP2A23 and CYP2A24) to human CYP2A6, and its functional role as a drug-metabolizing enzyme in the liver.
一种新的细胞色素P450（CYP），即CYP2A26，在食蟹猴中被鉴定和表征，食蟹猴是临床前研究中使用的动物物种之一。CYP2A26 cDNA推导的氨基酸序列与食蟹猴CYP2A23和CYP2A24以及人类CYP2A6和CYP2A13具有高度的序列同一性（91-95%）。系统发育分析表明，猕猴CYP2A（CYP2A26、CYP2A23和CYP2A24）与人类CYP2A的聚类关系最为密切，这与狗、大鼠和小鼠（其他也用于药物代谢研究的物种）的CYP2A不同。定量聚合酶链反应分析表明，CYP2A26 mRNA与CYP2A23和CYP2A24 mRNA一样，主要在肝脏中表达，通过免疫印迹也在肝脏中检测到了CYP2A蛋白。使用在大肠杆菌中异源表达的CYP2A26蛋白进行的药物代谢分析表明，CYP2A26催化香豆素7-羟基化反应，其表观K(m)低于CYP2A24，但与CYP2A6和CYP2A23的表观K(m)相似。这些结果表明食蟹猴CYP2A26（与CYP2A23和CYP2A24一起）与人类CYP2A6在进化上具有密切关系和功能相似性，并且它在肝脏中作为药物代谢酶发挥功能作用。
