Aryl hydrocarbon receptor-mediated suppression of expression of the low-molecular-weight prekininogen gene in mice.
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.
Nukaya
M
M
Laboratory of Drug Metabolism, Division of Pharmacobio-dynamics, Graduate School of Pharmaceutical Sciences, Hokkaido University, N12W6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan.
Takahashi
Y
Y
Gonzalez
F J
FJ
Kamataki
T
T
D000818:Animals; D020868:Gene Silencing / Q000187:drug effects; D007704:Kininogens / Q000096:biosynthesis / Q000235:genetics*; D007705:Kinins; D008297:Male; D008748:Methylcholanthrene / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics*; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D013723:Teratogens / Q000633:toxicity
D007704:Kininogens; D007705:Kinins; D000072317:Polychlorinated Dibenzodioxins; D011498:Protein Precursors; D018336:Receptors, Aryl Hydrocarbon; D013723:Teratogens; C046022:prekininogens; D008748:Methylcholanthrene