Induction of cytochrome P4501B1 in lung, liver and kidney of rats exposed to diesel exhaust
Induction of cytochrome P4501B1 in lung, liver and kidney of rats exposed to diesel exhaust
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DOI：
10.1093/carcin/22.12.2033
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发表时间：
2001-12-01
期刊：
影响因子：
4.7
通讯作者：
Yokoi, T
中科院分区：
文献类型：
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作者：
Hatanaka, N;Yamazaki, H;Yokoi, T
我们以前已经表明，柴油机尾气颗粒物（DEP）提取物（DEPE）和1-硝基芘的基因毒性激活的人细胞色素P450 1B 1在SOS/umu试验。在这项研究中，在体内诱导的P450家族1酶在大鼠暴露于柴油机尾气的mRNA水平，P450酶含量，药物氧化活性的微粒体和umu基因表达的典型P450底物和DEPE本身催化的微粒体方面进行了研究。将雄性Fischer 344大鼠（4周龄）暴露于0.3和3.0 mg/m3 DEP，每天12小时，持续4周;前一剂量对应于典型的每日空气颗粒浓度。暴露于0.3 mg/m（3）DEP后，大鼠肺和肝脏中P450 1B 1和P450 1A 1的mRNA水平显着增加1.1-1.4倍。柴油机排气颗粒提取物诱导umu基因在鼠伤寒沙门氏菌TA 1535/pSK 1002中表达的功能性P450系统的情况下，并进一步激活人重组P450 1B 1。使用过表达O-乙酰转移酶的沙门氏菌菌株，暴露于0.3 mg/m3 DEP时，肺、肝和肾微粒体对P450 1B 1标记化学品（1-硝基芘、1-氨基芘和DEPE）的遗传毒性激活分别增加1.7-4.2、1.4-1.5和1.0-1.3倍。暴露于3.0 mg/m3 DEP时，肺微粒体对3-氨基-1，4-二甲基-5H-吡啶并[4，3-B]吲哚（Trp-P-1; P450 1A 1的标记物）的活化和肝微粒体中P450 1A 2的含量略有增加。这是第一份报告表明，典型的每日污染物水平（0.3 mg颗粒/m3）的柴油机废气可以诱导大鼠的P450 1B 1，诱导的P450 1B 1可能催化DEP的遗传毒性激活。
We have shown previously that diesel exhaust particle (DEP) extracts (DEPE) and 1-nitropyrene were genotoxically activated by human cytochrome P450 1B1 in SOS/umu assay. In this study, the in vivo induction of P450 family 1 enzymes in rats by exposure to diesel exhaust was investigated with regard to mRNA levels, P450 enzyme content, drug oxidation activities in the microsomes and umu gene expression of typical P450 substrates and DEPE itself catalyzed by the microsomes. Male Fischer 344 rats (4 weeks old) were exposed to 0.3 and 3.0 mg/m(3) DEP for 12 h per day for 4 weeks; the former dose corresponded to the typical daily airborne particle concentration. The levels of mRNA of rat P450 1B1 and P450 1A1 in the lung and liver were significantly increased 1.1-1.4-fold by exposure to 0.3 mg/m(3) DEP. Diesel exhaust particle extracts induced umu gene expression in Salmonella typhimurium TA1535/pSK1002 in the absence of a functional P450 system and were further activated by human recombinant P450 1B1. Using an O-acetyltransferase overexpressing Salmonella strain, genotoxic activation of P450 1B1 marker chemicals (1-nitropyrene, 1-aminopyrene and DEPE) by lung, liver and kidney microsomes was increased 1.7-4.2-, 1.4-1.5- and 1.0-1.3-fold, respectively, by exposure to 0.3 mg/m(3) DEP. Activation of 3-amino-1,4-dimethyl-5H-pyrido [4,3-b]indole (Trp-P-1; marker for P450 1A1) by lung microsomes and the P450 1A2 content in liver microsomes were slightly increased by exposure to 3.0 mg/m(3) DEP. This is the first report to suggest that typical daily contaminant levels (0.3 mg particle/m(3)) of diesel exhaust can induce P450 1B1 in rats and that the induced P450 1B1 may catalyze the genotoxic activation of DEP.