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Int. J. Mol. Sci. 2014, 15(8), 14044-14057; doi:10.3390/ijms150814044

Mammalian Cytochrome P450-Dependent Metabolism of Polychlorinated Dibenzo-p-dioxins and Coplanar Polychlorinated Biphenyls

1
Research Center for Environmental Genomics, Kobe University, 1-1 Rokkodaicho, Nada-ku, Kobe, Hyogo 657-8501, Japan
2
Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, 3-3165 Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan
3
Biotechnology Research Center, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama 939-0398, Japan
*
Author to whom correspondence should be addressed.
Received: 13 May 2014 / Revised: 8 July 2014 / Accepted: 16 July 2014 / Published: 13 August 2014
(This article belongs to the Special Issue Mechanisms of Toxicity of Dioxins and Related Compounds)
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Abstract

Polychlorinated dibenzo-p-dioxins (PCDDs) and coplanar polychlorinated biphenyls (PCBs) contribute to dioxin toxicity in humans and wildlife after bioaccumulation through the food chain from the environment. The authors examined human and rat cytochrome P450 (CYP)-dependent metabolism of PCDDs and PCBs. A number of human CYP isoforms belonging to the CYP1 and CYP2 families showed remarkable activities toward low-chlorinated PCDDs. In particular, human CYP1A1, CYP1A2, and CYP1B1 showed high activities toward monoCDDs, diCDDs, and triCDDs but no detectable activity toward 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-tetraCDD). Large amino acids located at putative substrate-recognition sites and the F-G loop in rat CYP1A1 contributed to the successful metabolism of 2,3,7,8-tetraCDD. Rat, but not human, CYP1A1 metabolized 3,3',4,4',5-pentachlorobiphenyl (CB126) to two hydroxylated metabolites. These metabolites are probably less toxic than is CB126, due to their higher solubility. Homology models of human and rat CYP1A1s and CB126 docking studies indicated that two amino acid differences in the CB126-binding cavity were important for CB126 metabolism. In this review, the importance of CYPs in the metabolism of dioxins and PCBs in mammals and the species-based differences between humans and rats are described. In addition, the authors reveal the molecular mechanism behind the binding modes of dioxins and PCBs in the heme pocket of CYPs. View Full-Text
Keywords: CYP1A1; cytochrome P450 monooxygenase; hydroxylation; polychlorinated biphenyl; polychlorinated dibenzo-p-dioxin; sulfotransferase; UDP-glucuronosyltransferase CYP1A1; cytochrome P450 monooxygenase; hydroxylation; polychlorinated biphenyl; polychlorinated dibenzo-p-dioxin; sulfotransferase; UDP-glucuronosyltransferase
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MDPI and ACS Style

Inui, H.; Itoh, T.; Yamamoto, K.; Ikushiro, S.-I.; Sakaki, T. Mammalian Cytochrome P450-Dependent Metabolism of Polychlorinated Dibenzo-p-dioxins and Coplanar Polychlorinated Biphenyls. Int. J. Mol. Sci. 2014, 15, 14044-14057.

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