title: Structural-functional adaptations of porcine CYP1A1 to metabolize polychlorinated dibenzo-p-dioxins.
abstract: Polychlorinated dibenzo-p-dioxins (PCDDs) are widespread by-products of human industrial activity. They accumulate in tissues of animals and humans, exerting numerous adverse effects on different systems. In living organisms, dioxins are metabolized by enzymes of the cytochrome P450 family, including CYP1A1. Particular dioxin congeners differ in their toxicity level and ability to undergo biodegradation. Since the molecular mechanisms underlying dioxin susceptibility or resistance to biodegradation are unknown, in the present study the molecular interactions between five selected dioxins and porcine CYP1A1 protein were investigated. It was found that the ability of a dioxin to undergo CYP1A1-mediated degradation is associated mainly with the number and position of chlorine atoms in the dioxin molecule. Among all examined congeners, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) demonstrated the highest affinity to CYP1A1 and, at the same time, the greatest distance to the active site of the enzyme. Interestingly, in contrast to other dioxins, the binding of the TCDD molecule to the porcine CYP1A1 active site resulted in a rapid and continuous closure of substrate channels. All the information may help to explain the extended half-life of TCDD in living organisms as well as its high toxicity.
authors: Department of Animal Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Poland.
authors: Tomasz
authors: T
authors: Molcan
authors: Laboratory of Molecular Diagnostics, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Poland. Electronic address: sylwia.swigonska@uwm.edu.pl.
authors: Sylwia
authors: S
authors: Swigonska
authors: Department of Animal Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Poland.
authors: Karina
authors: K
authors: Orlowska
authors: Department of Botany and Nature Protection, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Poland.
authors: Kamil
authors: K
authors: Myszczynski
authors: Laboratory of Molecular Diagnostics, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Poland.
authors: Anna
authors: A
authors: Nynca
authors: Department of Animal Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Poland.
authors: Agnieszka
authors: A
authors: Sadowska
authors: Department of Animal Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Poland.
authors: Monika
authors: M
authors: Ruszkowska
authors: Department of Plant Physiology, Genetics and Biotechnology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Poland.
authors: Jan Pawel
authors: JP
authors: Jastrzebski
authors: Department of Animal Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Poland; Laboratory of Molecular Diagnostics, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Poland.
authors: Renata E
authors: RE
authors: Ciereszko
mesh_terms: D000818:Animals; D001665:Binding Sites; D001673:Biodegradation, Environmental; D020134:Catalytic Domain; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004147:Dioxins / Q000378:metabolism*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D000072317:Polychlorinated Dibenzodioxins / Q000032:analysis* / Q000378:metabolism; D011487:Protein Conformation; D013552:Swine
chemical_list: D018076:DNA, Complementary; D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D003577:Cytochrome P-450 Enzyme System; D019363:Cytochrome P-450 CYP1A1
keywords: Access channels; CYP1A1; Molecular docking; Molecular dynamics; PCDDs; Pig