Chain Reaction of Drug Metabolism -A Comprehensive Study on the Cooperative and Competitive Drug Metabolism by CYP Isoforms

细胞色素P450在人体药物代谢中起着关键作用，目前市面上90%以上的临床药物都能被5种细胞色素P450亚型代谢。在这项研究中，我们重点研究了药物代谢的五种异构体所起的连锁反应。虽然抗抑郁药阿米替林主要由CYP1A2、2C19和2D6代谢，但其结构类似于阿米替林的代谢物去甲替林在这些异构体中的代谢较差。另一方面，尽管在氨基酸序列和三维结构上与2C19具有同源性，但CYP2C9是阿米替林的不良代谢物。我们发现药物的特异性受第72位氨基酸残基的碱性调节。

Cytochrome P450s (CYPs) play a key role in human drug metabolism, and five CYP isoforms can metabolize more than 90% of clinical drugs in the market. In this study, we focused on a chain reaction of drug metabolism played by five isoforms. Although an anti-depressant amitriptyline is mainly metabolized by CYP1A2, 2C19, and 2D6, its metabolite nortriptyline, which is structurally similar to amitriptyline, was found to be poorly metabolized by these isoforms. On the other hand, CYP2C9 is a poor metabolizer of amitriptyline although it is homologous with 2C19 in amino acid sequence and three dimensional structure. We revealed that the drug specificity is regulated by the basicity of an amino acid residue at position 72.