Human cytochrome p450 2A13 efficiently metabolizes chemicals in air pollutants: Naphthalene, styrene, and toluene
Human cytochrome p450 2A13 efficiently metabolizes chemicals in air pollutants: Naphthalene, styrene, and toluene
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DOI：
10.1021/tx700325f
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发表时间：
2008-03-01
影响因子：
4.1
通讯作者：
Nakajima, Miki
中科院分区：
文献类型：
--
作者：
Fukami, Tatsuki;Katoh, Miki;Nakajima, Miki
人P450 2A 13是催化尼古丁代谢和4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）代谢活化的最有效酶。可以想象，P450 2A 13也代谢空气污染物中的化学物质，因为这种酶在呼吸道中高度表达。在这项研究中，我们研究了P450 2A 13可以代谢萘，苯乙烯和甲苯的可能性，这些物质包括在空气污染物和烟草烟雾中，尽管它们被P450 1A 2或2 E1代谢。我们发现，P450 2A 13催化1-和2-萘酚形成萘具有更高的固有清除率（kcat/Km）（分别为3.1和2.2倍）比P450 1A 2，也更有效地催化苯乙烯7，8-氧化物形成苯乙烯和苯甲醇形成甲苯比P450 2 E1。P450 2A 13与P450 2 E1的重叠底物特异性得到以下发现的支持：P450 2A 13催化氯唑沙宗6-羟基化（kcat/Km值高8倍）和对硝基苯酚2-羟基化（kcat/Km值高19倍），这是P450 2 E1的标记活性。因此，我们发现P450 2A 13代谢多种环境化学物质，并具有P450 1A 2和2 E1的重叠底物特异性，这表明P450 2A 13在呼吸道中与毒性或致癌性相关的环境化学物质的局部代谢中起重要作用。
Human P450 2A13 is the most efficient enzyme for catalyzing the metabolism of nicotine and metabolic activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). It is conceivable that P450 2A13 also metabolizes chemicals in air pollutants because this enzyme is highly expressed in the respiratory tract. In this study, we investigated the possibility that P450 2A13 can metabolize naphthalene, styrene, and toluene, which are included in air pollutants as well as tobacco smoke, although they were known to be metabolized by P450 1A2 or 2E1. We found that P450 2A13 catalyzed 1- and 2-naphthol formations from naphthalene with higher intrinsic clearances (kcat/Km) (3.1- and 2.2-fold, respectively) than P450 1A2 and also more efficiently catalyzed the styrene 7,8-oxide formation from styrene and the benzylalcohol formation from toluene than P450 2E1. The overlapping substrate specificity of P450 2A13 with P450 2E1 was supported by the finding that P450 2A13 catalyzed chlorzoxazone 6-hydroxylation (8-fold higher value of kcat/Km) and p-nitrophenol 2-hydroxylation (19-fold higher value of kcat/Km), which are marker activities of P450 2E1. Thus, we found that P450 2A13 metabolizes diverse environmental chemicals and has overlapping substrate specificities of P450 1A2 and 2E1, suggesting that P450 2A13 plays important roles in the local metabolism of environmental chemicals in the respiratory tract related to toxicity or carcinogenicity.