|show drug details|
|2,3,7,8-Tetra polychlorinated dibenzo-p-dioxin|
|2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (SEE ALSO TRANSGENIC MODEL EVALUATION|
|2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (SEE ALSO TRANSGENIC MODEL EVALUATION (2,3,7,8-TETRACHLORODIBENZODIOXIN))|
|2,3,7,8-Tetrachlorodibenzo-p-dioxin [Dioxin and dioxin-like compounds]|
|5-19-02-00041 (Beilstein Handbook Reference)|
|Dioxin (herbicide contaminant)|
|TEF TRANSGENICS (TCDD)|
|TOXIC EQUIVALENCY FACTOR EVALUATION (TCDD) (SEE ALSO TCDD & TRANSGENIC MODEL EVALUATION)|
|TRANSGENIC MODEL EVALUATION (2,3,7,8-TETRACHLORODIBENZODIOXIN)|
|Ki: ||Kd:||Ic 50:||Ec50/Ic50:|
CYP1A1 induction and CYP3A4 inhibition by the fungicide imazalil in the human intestinal Caco-2 cells-comparison with other conazole pesticides.. Thérèse Sergent; Isabelle Dupont; Coralie Jassogne; Laurence Ribonnet; Edwige van der Heiden; Marie-Louise Scippo; Marc Muller; Dan McAlister; Luc Pussemier; Yvan Larondelle; Yves-Jacques Schneider (2009) Toxicology letters display abstract
Imazalil (IMA) is a widely used imidazole-antifungal pesticide and, therefore, a food contaminant. This compound is also used as a drug (enilconazole). As intestine is the first site of exposure to ingested drugs and pollutants, we have investigated the effects of IMA, at realistic intestinal concentrations, on xenobiotic-metabolizing enzymes and efflux pumps by using Caco-2 cells, as a validated in vitro model of the human intestinal absorptive epithelium. For comparison, other conazole fungicides, i.e. ketoconazole, propiconazole and tebuconazole, were also studied. IMA induced cytochrome P450 (CYP) 1A1 activity to the same extent as benzo(a)pyrene (B(a)P) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in a dose- and time-dependent manner. Cell-free aryl hydrocarbon receptor (AhR) binding assay and reporter gene assay suggested that IMA is not an AhR-ligand, implying that IMA-mediated induction should involve an AhR-independent pathway. Moreover, IMA strongly inhibited the CYP3A4 activity in 1,25-vitamin D(3)-induced Caco-2 cells. The other fungicides had weak or nil effects on CYP activities. Study of the apical efflux pump activities revealed that ketoconazole inhibited both P-glycoprotein (Pgp) and multidrug resistance-associated protein 2 (MRP-2) or breast cancer resistance protein (BCRP), whereas IMA and other fungicides did not. Our results imply that coingestion of IMA-contaminated food and CYP3A4- or CYP1A1-metabolizable drugs or chemicals could lead to drug bioavailability modulation or toxicological interactions, with possible adverse effects for human health.
Induction of cytochrome P-450 1A1 by omeprazole in human HepG2 cells is protein tyrosine kinase-dependent and is not inhibited by alpha-naphthoflavone.. H Kikuchi; A Hossain; H Yoshida; S Kobayashi (1998) Archives of biochemistry and biophysics display abstract
Benzimidazole compounds, such as omeprazole and thiabendazole, are a different type of CYP1A1 inducer from Ah receptor-ligands, such as TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) and 3-methylcholanthrene. In HepG2 cells, the commonly used tyrosine kinase inhibitors, herbimycin-A and a series of tyrphostins, inhibited the induction of CYP1A1 produced by treatment with TCDD. Genistein, another type of tyrosine kinase inhibitor, inhibited the induction of CYP1A1 whether it was produced by omeprazole or TCDD; however, this inhibition was caused by a dual effect of genistein, that is an anti-tyrosine kinase and an anti-topoisomerase I effect. An antagonist of Ah receptor, alpha-naphthoflavone (0.1-10 microM), and 3'-methoxy-4'-aminoflavone (1 microM), did not inhibit the induction of CYP1A1 produced in HepG2 cells by omeprazole, but both of them did inhibit that produced by TCDD. In one of a number of human lung tumor cell lines, S6T, the inducibility of CYP1A1 was high by TCDD, whereas the inducibility by omeprazole was low. Thus, omeprazole appears to induce CYP1A1 by initiating a protein tyrosine kinase-mediated signal transduction pathway, a different pathway from that inhibited by TCDD.