In vitro metabolism of naphthalene by human liver microsomal cytochrome P450 enzymes
In vitro metabolism of naphthalene by human liver microsomal cytochrome P450 enzymes
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DOI：
10.1124/dmd.105.005785
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发表时间：
2006-01-01
影响因子：
3.9
通讯作者：
Hodgson, E
中科院分区：
文献类型：
--
作者：
Cho, TM;Rose, RL;Hodgson, E
多环芳烃萘是一种环境污染物，是喷气燃料的一种成分，自2000年以来已被重新归类为潜在的人类致癌物质。几乎没有关于人体体外新陈代谢的研究，这些研究主要集中在肺代谢上。目前的研究是通过人细胞色素P450来表征萘的代谢。人肝微粒子(PHLMS)的代谢产物为反式-1，2-二氢-1，2-萘二酚(二氢二酚)、1-萘酚和2-萘酚。代谢产物产生的Km值分别为23、40和116muM，V-max值分别为2860、268和22pmol/mg蛋白质/分钟。对苯代谢的P450亚型进行筛选，结果表明，CYP1A2是产生二氢二酚和1-萘酚的最有效的亚型，而CYP3A4是产生2-萘酚的最有效的亚型。还研究了萘的初级代谢物的代谢，以鉴定次级代谢物。而2-萘酚很容易被PHLMS代谢生成2，6-和1，7-二羟基萘，二氢二酚和1-萘酚是PHLMS的低效底物。利用一系列人P450亚型进一步研究二氢二酚和1-萘酚的代谢。从1-萘酚中观察到1，4-萘酚和4种次要的未知代谢物，并确定CYP1A2和2D6*1是生产1，4-萘酚的最有活性的异构体。二氢二醇被P450亚型代谢成三种次要的未知代谢产物，其中对该底物的活性最强的是细胞色素P450 3A4和细胞色素P2A6。P450亚型对二氢二酚的代谢低于1-萘酚。这些研究确定了由PHLMS和P450亚型产生的初级和次级代谢物。
The polycyclic aromatic hydrocarbon naphthalene is an environmental pollutant, a component of jet fuel, and, since 2000, has been reclassified as a potential human carcinogen. Few studies of the in vitro human metabolism of naphthalene are available, and these focus primarily on lung metabolism. The current studies were performed to characterize naphthalene metabolism by human cytochromes P450. Naphthalene metabolites from pooled human liver microsomes ( pHLMs) were trans-1,2-dihydro-1,2-naphthalenediol ( dihydrodiol), 1-naphthol, and 2-naphthol. Metabolite production generated Km values of 23, 40, and 116 mu M and V-max values of 2860, 268, and 22 pmol/mg protein/min, respectively. P450 isoform screening of naphthalene metabolism identified CYP1A2 as the most efficient isoform for producing dihydrodiol and 1-naphthol, and CYP3A4 as the most effective for 2-naphthol production. Metabolism of the primary metabolites of naphthalene was also studied to identify secondary metabolites. Whereas 2-naphthol was readily metabolized by pHLMs to produce 2,6- and 1,7-dihydroxynaphthalene, dihydrodiol and 1-naphthol were inefficient substrates for pHLMs. A series of human P450 isoforms was used to further explore the metabolism of dihydrodiol and 1-naphthol. 1,4-Naphthoquinone and four minor unknown metabolites from 1-naphthol were observed, and CYP1A2 and 2D6*1 were identified as the most active isoforms for the production of 1,4-naphthoquinone. Dihydrodiol was metabolized by P450 isoforms to three minor unidentified metabolites with CYP3A4 and CYP2A6 having the greatest activity toward this substrate. The metabolism of dihydrodiol by P450 isoforms was lower than that of 1-naphthol. These studies identify primary and secondary metabolites of naphthalene produced by pHLMs and P450 isoforms.