Sagredo Carlos, Øvrebø Steinar, Haugen Aage, Fujii-Kuriyama Yoshiaki, Baera Rita, Botnen Ingrid V, Mollerup Steen
Section for Toxicology, National Institute of Occupational Health, P.O. Box 8149 Dep., N-0033 Oslo, Norway.
Toxicol Lett. 2006 Dec 15;167(3):173-82. doi: 10.1016/j.toxlet.2006.09.005. Epub 2006 Oct 16.
Benzo[a]pyrene (BP) is an ubiquitous environmental pollutant with potent mutagenic and carcinogenic properties. The Ah receptor (Ahr) is involved in the metabolic activation of BP and is therefore important in the induction of chemical carcinogenesis. In this study, the relationship between Ahr genotype and biotransformation of BP in internal organs was investigated in Ahr (+/+), Ahr (+/-) and Ahr (-/-) mice. The mice were treated with BP (100mg/kg) by gavage. Gene expression was measured after 24h by real-time RT-PCR and showed induction of Cyp1a1 in liver and lung, and Cyp1b1 in lung in both Ahr (+/+) and Ahr (+/-). No induction of the Cyp genes was observed in the Ahr (-/-). There was a significant basal expression of Cyp1b1 in the liver of all genotypes, and this expression was independent of the BP exposure. Analyzed by HPLC-fluorescence, there were increased levels of protein and DNA adducts, metabolites, conjugates and unmetabolized BP in the internal organs of Ahr (-/-) as compared to Ahr (+/+) and Ahr (+/-) mice. This may be partly explained by a delayed bioactivation of BP in the Ahr deficient mice. The BP metabolism observed in the Ahr (-/-) mice is also evidence of an Ahr independent biotransformation of BP.
苯并[a]芘（BP）是一种普遍存在的环境污染物，具有强大的致突变和致癌特性。芳烃受体（Ahr）参与BP的代谢活化，因此在化学致癌作用的诱导中起重要作用。在本研究中，在Ahr（+/+）、Ahr（+/-）和Ahr（-/-）小鼠中研究了Ahr基因型与BP在内脏中的生物转化之间的关系。通过灌胃给小鼠施用BP（100mg/kg）。24小时后通过实时RT-PCR测量基因表达，结果显示在Ahr（+/+）和Ahr（+/-）小鼠的肝脏和肺中Cyp1a1被诱导，在肺中Cyp1b1被诱导。在Ahr（-/-）小鼠中未观察到Cyp基因的诱导。在所有基因型的肝脏中Cyp1b1都有显著的基础表达，且这种表达与BP暴露无关。通过HPLC-荧光分析，与Ahr（+/+）和Ahr（+/-）小鼠相比，Ahr（-/-）小鼠内脏中蛋白质和DNA加合物、代谢物、共轭物和未代谢BP的水平升高。这可能部分是由于Ahr缺陷小鼠中BP的生物活化延迟所致。在Ahr（-/-）小鼠中观察到的BP代谢也是BP的Ahr非依赖性生物转化的证据。
