> link between IBD and Dioxins?
[The drug salicylamide is an antagonist of the aryl hydrocarbon
receptor that inhibits signal transduction induced by TCDD]
TCDD is a widespread environmental contaminant, that has been linked
with a variety of deleterious effects on human health, including
increased cancer rates and reproductive anomalies. The detrimental
effects of TCDD are mediated via the aryl hydrocarbon receptor (AhR),
a transcription factor that regulates the expression of the carcinogen-
activating enzymes cytochromes P-450 (CYP) 1A1, 1A2, and 1B1. In the
present study, we examined the ability of synthetic derivatives of
salicylic acid to affect TCDD-stimulated AhR-mediated signal
transduction in human hepatoma HepG2 cells. Salicylamide (SAL), an
analgesic drug, caused a potent and long-lasting inhibition of TCDD-
induced CYP enzyme activity. Acetylsalicylic acid (aspirin) and the
naturally occurring phytochemical salicylic acid had no effect on CYP
activity. SAL inhibited the increase in CYP1A1, -1A2, and -1B1 mRNA
levels that occurs on exposure to TCDD. TCDD-induced transcription of
these genes was also inhibited by SAL, but not by aspirin or salicylic
acid, as demonstrated by luciferase re****ter assays. The transcription
of the CYP1 family of genes is regulated by the interaction of TCDD-
activated AhR with the xenobiotic-responsive element present in the
promoter regions of these genes. As shown by electrophoretic mobility
****ft assay, SAL completely blocked the binding of TCDD-activated AhR
to the xenobiotic responsive element. Also, SAL substantially blocked
the binding of TCDD to the cytosolic AhR. These results demonstrate
that SAL, a commonly used analgesic, is a potent inhibitor of AhR-
mediated signal transduction, and may be an effective agent in the
prevention of TCDD-associated disease. PMID: 14729655
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