The metabolism of 1-nitropyrene by human cytochromes P450.
The metabolism of 1-nitropyrene by human cytochromes P450.
复制标题
人细胞色素 P450 对 1-硝基芘的代谢。
DOI：
10.1093/carcin/11.9.1539
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发表时间：
1990
期刊：
影响因子：
4.7
通讯作者：
Gonzalez,FJ
中科院分区：
文献类型：
--
作者：
Howard,PC;Aoyama,T;Bauer,SL;Gelboin,HV;Gonzalez,FJ
用Vacciniavirus在HepG 2细胞中表达P450 cDNA，研究了人细胞色素P450的特异性形式对[3 H]1-硝基芘的代谢。用含人P450 cDNA的重组痘苗病毒（P450 IA 2、IIA 3、IIB 7、IIC 8、IIC 9、IID 6、IIE 1、IIF 1、IIIA 3、IIIA 4、IIIA 5和IVB 1）分别感染细胞裂解物。只有IIIA 3和IIIA 4在1-硝基芘的C-氧化中表现出显著的活性。两种P450形式的主要代谢产物均为1-硝基芘-3-醇，其产率至少是1-硝基芘-6-醇和1-硝基芘-8-醇的混合物或K区二氢吲哚的4倍。这与许多物种中的代谢相反，在许多物种中，6-醇和8-醇的形成主导于3-醇的形成。事实上，在大鼠和兔子中，P450的形式与IIIA P450完全不同，P450催化这种污染物的大部分代谢。这是第一次证明个人P450形式在这类重要的环境污染物中代表性化学物质代谢中的作用。这些观察结果在人类对这些化学品的总体致癌风险中的重要性仍有待确定。这些研究进一步确立了硝化多环芳烃代谢的显著种属差异。
The metabolism of [3H]1-nitropyrene by specific forms of human cytochrome P450 was investigatedin vitrousingVacciniavirus expression of P450 cDNAs in HepG2 cells. Cell lysates were invected individually with recombinantVacciniavirus containing human P450 cDNA (P450 IA2, IIA3, IIB7, IIC8, IIC9, IID6, IIE1, IIF1, IIIA3, IIIA4, IIIA5 and IVB1). Only IIIA3 and IIIA4 demonstrated significant activity in the C-oxidationof 1-nitropyrene. The principal metabolite from both P450 forms was 1-nitropyren-3-ol, produced in at least 4-fold greaterabundance than the mixture of 1-nitropyren-6-ol and 1-nitropyren-8-ol, or the K-region dihydrodlols. This is in contrast to the metabolism in many species where 6-ol and 8-ol formation predominate over 3-ol formation. In fact, in rats and rabbits, P450 forms quite distinct from the IIIA P450s catalyze the majority of the metabolism of this pollutant. This is the first demonstration of the role of individual human P450 forms in the metabolism of a representative chemical in this Important class of environmental pollutants. The importance of these observations in the overall carcinogenic risk of humans tothese chemicals remains to be established. These studies further more establish a marked species difference in the metabolism of nitrated polycycic aromatic hydrocarbons.