Nukaya M, Takahashi Y, Gonzalez F J, Kamataki T
Laboratory of Drug Metabolism, Division of Pharmacobio-dynamics, Graduate School of Pharmaceutical Sciences, Hokkaido University, N12W6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan.
Biochem Biophys Res Commun. 2001 Sep 14;287(1):301-4. doi: 10.1006/bbrc.2001.5581.
Differential mRNA display showed that a cDNA band disappeared after treatment of mice with 3-methylcholanthrene (MC). The cDNA encoded low-molecular-weight (LMW) prekininogen, known to be the precursor of a potent vasodilator, bradykinin. MC is generally known to bind to aryl hydrocarbon receptor (AhR) as an initial event to cause effects in vivo. In accordance with the results, Northern blot analysis for LMW prekininogen mRNA using total RNAs from wild-type and AhR-null mice indicated that the suppression of the mRNA expression by MC was seen in wild-type mice but not in AhR-null mice. The expression of LMW prekininogen mRNA was almost completely lost within 1 h after treatment of mice with MC, while a clear increase of CYP1A2 mRNA, as a positive control, was noted 4 h after the treatment. The plasma concentration of bradykinin released from LMW prekininogen was decreased by MC in wild-type mice, but not in AhR-null mice. Based on these results, we conclude that AhR inhibits bradykinin synthesis in mice via suppression of the expression of LMW prekininogen. Possible mechanism(s) responsible for hypertension caused by treatment of mice with MC is also discussed.
差异mRNA显示表明，用3-甲基胆蒽（MC）处理小鼠后，一条cDNA条带消失。该cDNA编码低分子量（LMW）前激肽原，已知它是一种强效血管舒张剂缓激肽的前体。一般认为，MC作为体内产生效应的初始事件与芳烃受体（AhR）结合。根据这些结果，使用野生型和AhR基因敲除小鼠的总RNA对LMW前激肽原mRNA进行Northern印迹分析表明，MC对mRNA表达的抑制在野生型小鼠中可见，而在AhR基因敲除小鼠中则未出现。在用MC处理小鼠后1小时内，LMW前激肽原mRNA的表达几乎完全丧失，而作为阳性对照的CYP1A2 mRNA在处理后4小时出现明显增加。在野生型小鼠中，MC降低了从LMW前激肽原释放的缓激肽的血浆浓度，但在AhR基因敲除小鼠中则未降低。基于这些结果，我们得出结论，AhR通过抑制LMW前激肽原的表达来抑制小鼠体内缓激肽的合成。本文还讨论了用MC处理小鼠导致高血压的可能机制。
