CYP2A13 metabolizes the substrates of human CYP1A2, phenacetin, and theophylline
CYP2A13 metabolizes the substrates of human CYP1A2, phenacetin, and theophylline
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DOI：
10.1124/dmd.106.011064
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发表时间：
2007-03-01
影响因子：
3.9
通讯作者：
Yokoi, Tsuyoshi
中科院分区：
文献类型：
--
作者：
Fukami, Tatsuki;Nakajima, Miki;Yokoi, Tsuyoshi
人细胞色素CYP 2A 13显示与CYP 2A 6重叠的底物特异性，催化香豆素、尼古丁、可替宁和4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮的代谢。最近，人们发现CYP 2A 13可以催化4-氨基联苯和黄曲霉毒素B1的代谢活化，而这些代谢活化已知是由人CYP 1A 2催化的。在本研究中，我们研究了CYP 2A 13的底物特异性。研究表明，CYP 2A 13可催化乙氧基试卤灵O-脱乙基化、甲氧基试卤灵O-脱甲基化和非那西丁O-脱乙基化，这些反应被用作人CYP 1A 2的标记活性。虽然CYP 2A 13的前两个反应的固有清除率（V-max/K-m）远低于CYP 1A 2，但CYP 2A 13的最后一个反应的值是CYP 1A 2的2倍。特别令人感兴趣的是，CYP 2A 13对非那西丁的亲和力高于CYP 1A 2。相比之下，CYP 2A 6几乎不催化这些反应，尽管与CYP 2A 13的氨基酸同一性高达93.5%。此外，我们发现CYP 2A 13可以催化茶碱8-羟基化和3-去甲基化，这是已知主要由人CYP 1A 2催化的，尽管固有清除率约为CYP 1A 2的十分之一。CYP 2A 13不会促进这些药物的全身清除，因为CYP 2A 13在人肝脏中几乎不表达。然而，它可能在肺或气管等局部组织的代谢中发挥作用。总之，本研究的结果可以扩展我们对CYP 2A 13底物特异性的理解。
Human cytochrome CYP2A13 shows overlapping substrate specificity with CYP2A6, catalyzing the metabolism of coumarin, nicotine, cotinine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Recently, it was found that CYP2A13 could catalyze the metabolic activations of 4-aminobiphenyl and aflatoxin B1, which are known to be catalyzed by human CYP1A2. In the present study, we investigated the substrate specificity of CYP2A13. It was shown that CYP2A13 could catalyze ethoxyresorufin O-deethylation, methoxyresorufin O-demethylation, and phenacetin O-deethylation, which are used as marker activities for human CYP1A2. Although the intrinsic clearances (V-max/K-m) of the two former reactions by CYP2A13 were much lower than that of CYP1A2, the value of the last reaction by CYP2A13 was 2-fold higher than that of CYP1A2. Of particular interest was that CYP2A13 has higher affinity toward phenacetin than CYP1A2. In contrast, CYP2A6 hardly catalyzed these reactions, although the amino acid identity with CYP2A13 is as high as 93.5%. Furthermore, we found that CYP2A13 can catalyze theophylline 8-hydroxylation and 3-demethylation, which are known to be mainly catalyzed by human CYP1A2, although the intrinsic clearances were approximately one-tenth that of CYP1A2. CYP2A13 would not contribute to the systemic clearance of these drugs because CYP2A13 is hardly expressed in human liver. However, it may play a role in metabolism in local tissues such as lung or trachea. In conclusion, the results of the present study could extend our understanding of the substrate specificity of CYP2A13.