2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced porphyria in genetically inbred mice: Partial antagonism and mechanistic studies

Aryl hydrocarbon receptor-mediated inhibition of LNCaP prostate cancer cell growth and hormone-induced transactivation

“…Both the AhR and Arnt proteins are expressed LNCaP cells, and CYP1A1 protein is induced by TCDD and 6-MCDF. The induction of CYP1A1 by 6-MCDF was surprising since previous studies in breast cancer cells, rodent mammary tumors, and rodent liver show that this compound only weakly induces CYP1A1, and in cotreatment studies (TCDD + 6-MCDF), 6-MCDF inhibits induction of CYP1A1 by TCDD [38][39][40][41][42][43][44][45]. Treatment of LNCaP cells with TCDD resulted in decreased AhR protein expression, and this is consistent with studies in other cell lines where TCDD activates proteasome-dependent degradation of the AhR [45,[65][66][67].…”

“…Moreover, many of these compounds such as synthetic retinoids, bioflavonoids, indole-3-carbinol and diindolylmethane (DIM) exhibit chemoprotective and anticarcinogenic properties in laboratory animal studies [58][59][60][61][62][63]. 6-MCDF is an example of a relatively non-toxic synthetic AhR agonist/antagonist that inhibits several TCDD-induced toxic responses including cleft palate, immunotoxicity and porphyria in mice and CYP1A1 in both in vivo and in vitro models [38][39][40][41]. However, 6-MCDF exhibits selective AhR agonist activity as an antiestrogen and inhibits E2-dependent mammary tumor protein levels in whole cell lysates were determined by Western blot analysis as described in Section 2. p27 protein was also determined for this experiment; p27 was essentially unchanged in all of the treatment groups and serves as a loading control for this experiment.…”

“…Alternate substituted (1,3,6,8-or 2,4,6,8-) alkyl polychlorinated dibenzofurans, typified by 6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF), are relatively non-toxic and inhibit prototypical AhR-mediated toxic responses in rodent models (i.e., AhR antagonists) but exhibit selective AhR-dependent antiestrogenic and antitumorigenic activities in mammary tumor models [38][39][40][41][42][43][44][45][46]. 6-MCDF also inhibits growth of some ER-negative breast cancer [47] and pancreatic cancer cells [35].…”

Comparisons of differential gene expression elicited by TCDD, PCB126, βNF, or ICZ in mouse hepatoma Hepa1c1c7 cells and C57BL/6 mouse liver

“…TCDD-induced enzyme expression and/or activity (AHH, EROD, and Cyp1a1 expression) (Astroff and Safe, 1989; Astroff et al, 1988; Bannister et al, 1989; Harris et al, 1989; Kim et al, 2006), AhR binding (Gasiewicz and Rucci, 1991), ER binding down-regulation (Romkes et al, 1987), and TCDD-induced porphyria (Yao and Safe, 1989), immunotoxicity (Davis and Safe, 1988; Dickerson et al, 1990), cleft palate, and hydronephrosis (Bannister et al, 1989; Biegel et al, 1989) can be antagonized by SAhRMs. More recently, SAhRMS that modulate hematopoietic progenitor expansion (Boitano et al, 2010), repress cytokine-mediated induction of complement factor genes (Murray et al, 2011), antagonize cytokine-mediated inflammatory signaling (Murray et al, 2010), and inhibit tumor growth (Jin et al, 2012; Safe et al, 1999; Yin et al, 2012) in absence of canonical DRE-elicited transcription have also been developed.…”

Aryl Hydrocarbon Receptor (AHR)-Active Pharmaceuticals Are Selective AHR Modulators in MDA-MB-468 and BT474 Breast Cancer Cells

“…The molecular mechanism of action of AHR ligands has been extensively investigated, and ligand-dependent activation of the AHR generally results in formation of a nuclear AHR-AHR nuclear translocator heterodimer, which binds dioxin responsive elements (DREs) in target gene promoters to activate transcription (Denison et al, 2011). Our studies initially focused on the development of AHR antagonists that inhibited TCDD-induced toxicity, and we identified 3, as an inhibitor of TCDDinduced CYP1A1, porphyria, immunotoxicity, and teratogenicity in rodent models (Astroff et al, 1988;Bannister et al, 1989;Harris et al, 1989;Yao and Safe, 1989). However, MCDF did not inhibit TCDD-induced antiestrogenic effects in the rodent uterus or human breast cancer cells but acted as an AHR agonist (Astroff and Safe, 1991;Zacharewski et al, 1992), and subsequent studies showed that MCDF also inhibited ERpositive and ER-negative breast cancer cell and tumor growth (McDougal et al, 2001;Zhang et al, 2009Zhang et al, , 2012.…”