The Drug Salicylamide Is an Antagonist of the Aryl Hydrocarbon Receptor That Inhibits Signal Transduction Induced by 2,3,7,8-Tetrachlorodibenzo- p -dioxin

Abstract

ABSTRACT2,3,7,8-Tetrachlorodibenzo-p-dioxin (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 AhRmediated 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 reporter 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 shift 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.

Sulforaphane inhibits CYP1A1 activity and promotes genotoxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in vitro

“…Another possible cause is that SFN can compete with TCDD in binding to AhR-heat shock protein 90 dimer. Consequently, the signal transduction leading to the expression of CYP1A1 is blocked (Henry et al, 1999;MacDonald et al, 2004). In present study, the results of molecular docking also revealed that SFN can bind to AhR and CYP1A1 by hydrogen bonds, respectively (Fig.…”

Transcriptomic analyses of genes differentially expressed by high-risk and low-risk human papilloma virus E6 oncoproteins

“…CTNNA1 has been shown to be downregulated in human squamous cell carcinoma of the oesophagus [15,27], our microarray data showed upregulation of the gene while the qRT-PCR showed a downregulation in 11E6 and further downregulation in 18E6 compared to mock which suggest that 18E6 might be more potent in inhibiting the CTNNA1 expression than 11E6. CYP1B1 is a metabolic enzyme involved in degradation of environmental carcinogens like benzo(a)-pyrene and other polycyclic hydrocarbons (PAHs) present in environmental pollution and cigarette smoke which forms DNA adducts [22], and converts them to soluble products which are excreted out. Elevated CYP1B1 expression may result in a greater load of reactive oxygen intermediates (ROMs) causing genotoxic stress and tumour initiation [12,37].…”

2-(4-Amino-3-methylphenyl)-5-fluorobenzothiazole is a ligand and shows species-specific partial agonism of the aryl hydrocarbon receptor

“…Schild assay has previously been used to demonstrated that PCB 128 is a competitive antagonist of the fish AhR (Hestermann et al, 2000). It is apparent that several AhR ligands exhibit both agonistic and antagonistic activities ) (MacDonald et al, 2004) (de Medina et al, 2005, and classical receptor theory predicts that partial agonists will cause different levels of response, dependent upon receptor number and receptor-coupling (Kenakin, 1997); indeed, cell-specific response to partial agonists of AhR has been demonstrated (Zhang et al, 2003). The relative quantification of these activities is essential for understanding how AhR receptor number and coupling are related to the physiological and toxicological consequences of exposure to AhR ligands.…”