Quantitative analysis of benzo[a]pyrene biotransformation and adduct formation in Ahr knockout mice

Sex differences in susceptibility to PAHs is an intrinsic property of human lung adenocarcinoma cells

“…The AHR-dependent regulation of expression is however confirmed by this study, which reveals significant correlations between expression of AHR mRNA and CYP1A1 mRNA, and between AHR mRNA and CYP1B1 mRNA. Studies with mice lacking AHR and RNA interference experiments in human cell lines show that AHR is essential for both basal and induced expression levels of CYP1A1 [32][33][34]. CYP1A1 is predominantly, if not exclusively, regulated by the AHR pathway, while CYP1B1, in addition to the AHR-ARNT complex, is also dependent on several key transcription factors like SP1, CREB1 and ER [35,36].…”

Evidence for Ligand-Mediated Selective Modulation of Aryl Hydrocarbon Receptor Activity

“…Whereas evolutionarily and structurally dissimilar to the steroid nuclear hormone receptor family, AHR, the only known ligand-activated member of the basic helix-loop-helix/PAS family of transcription factors behaves in an analogous fashion to elicit gene induction (Beischlag et al, 2008). Binding of an agonist (e.g., TCDD) increases the affinity of AHR for its cognate response element and facilitates the expression of AHR-responsive genes, principally members of the CYP1 P450 family, often leading to genotoxic stress or endocrine disruption (Safe, 1995;Sagredo et al, 2006). Despite the functional similarity between AHR and the nuclear receptor family, the notion of therapeutic modulation of AHR has, with the notable exception of its ability to antagonize ER function and mitigate hormone-sensitive tumor growth, largely been overlooked (Safe and McDougal, 2002).…”

“…Although illustrating the involvement of AHR, the use of polycyclic hydrocarbon agonists is not therapeutically viable because of the perceived inherent toxicity associated with AHR activation. Indeed, the AHR has a dubious reputation as a mediator of various modes of toxicity, including the conversion of procarcinogens into genotoxic intermediates through enhanced phase I bioactivity (Sagredo et al, 2006). Deleterious effects result from ligand-activated AHR in combination with its dimerization partner ARNT binding to DREs within AHR target genes, thus facilitating the expression of downstream effectors.…”

Tocopherol transfer protein deficiency modifies nuclear receptor transcriptional networks in lungs: Modulation by cigarette smoke in vivo

“…Previous studies have shown that CS inhalation increases activities of enzymes encoded by cyp1 genes (Gairola, 1987). Cyp1a1 and 1b1 induction decreases benzopyrene induced formation of protein and DNA adducts, metabolites, conjugates and unmetabolized benzo[a]pyrene (Sagredo et al, 2006) suggesting possible mechanisms by which they may provide protective functions against carcinogens. Cyp1a1 and cyp1b1 are induced in Clara cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin, a high affinity ligand for AhR (Chang et al, 2006).…”