Metabolism of nicotine and cotinine by human cytochrome P450 2A13
Metabolism of nicotine and cotinine by human cytochrome P450 2A13
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DOI：
10.1124/dmd.104.002105
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发表时间：
2005-02-01
影响因子：
3.9
通讯作者：
Hong, JY
中科院分区：
文献类型：
--
作者：
Bao, ZP;He, XY;Hong, JY
尼古丁是烟草的主要成分，在吸烟成瘾中起着关键作用。在人体中，尼古丁主要代谢为可替宁，可替宁进一步代谢为反式-3 '-羟基可替宁。最近，我们已经证明异源表达的人CYP 2A 13在尼古丁衍生致癌物4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）的代谢中具有高度活性。在本研究中，发现尼古丁和N '-亚硝基去甲尼古丁（NNN）竞争性抑制CYP 2A 13催化的NNK代谢，表明尼古丁和NNN也是CYP 2A 13的底物。我们进一步证明，人CYP 2A 13确实是催化尼古丁C-氧化形成可替宁的有效酶，表观Km和V-max值分别为20.2 μ M和8.7 pmol/min/pmol。CYP 2A 13还催化可替宁的3 '-羟基化形成反式-3'-羟基可替宁，表观K-m和V-max值分别为45.2 μ M和0.7 pmol/min/pmol。CYP 2A 13催化的尼古丁和可替宁体内代谢的重要性仍有待确定。
Nicotine, a major constituent of tobacco, plays a critical role in smoking addiction. In humans, nicotine is primarily metabolized to cotinine, which is further metabolized to trans-3'-hydroxycotinine. Recently, we have demonstrated that heterologously expressed human CYP2A13 is highly active in the metabolism of 4-(methylnitrosamino)-1-( 3-pyridyl)-1-butanone (NNK), a nicotine-derived carcinogen. In the present study, CYP2A13-catalyzed NNK metabolism was found to be inhibited competitively by nicotine and N'-nitrosonornicotine (NNN), suggesting that both nicotine and NNN are also substrates of CYP2A13. We have further demonstrated that human CYP2A13 is indeed an efficient enzyme in catalyzing C-oxidation of nicotine to form cotinine, with the apparent Km and V-max values of 20.2 muM and 8.7 pmol/min/pmol, respectively. CYP2A13 also catalyzes the 3'-hydroxylation of cotinine to form trans-3'-hydroxycotinine, with the apparent K-m and V-max values of 45.2 muM and 0.7 pmol/min/pmol, respectively. The importance of CYP2A13-catalyzed nicotine and cotinine metabolism in vivo remains to be determined.