Mammalian Cytochrome P450-Dependent Metabolism of Polychlorinated Dibenzo-p-dioxins and Coplanar Polychlorinated Biphenyls
Abstract
:1. Introduction
2. Yeast Expression System for Mammalian Cytochrome P450 (CYP) Isoforms
3. Metabolism of Polychlorinated Dibenzo-p-dioxins (PCDDs) by Human and Rat CYPs
3.1. Metabolism of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (tetraCDD) in Humans
3.2. CYP-Dependent Metabolism of PCDDs
3.3. Binding of Tetra- and PentaCDDs to the Substrate-Binding Pocket of CYPs
3.4. Further Metabolism of PCDDs after CYP-Dependent Hydroxylation
3.5. Metabolism of 8-OH-2,3,7-triCDD by Human Recombinant UDP Glucuronosyltransferases (UGTs)
3.6. Successive Metabolism of 2,3,7-triCDD by CYPs and UGTs in Human Liver Microsomes
3.7. Species-Based Difference in CYP-Dependent Metabolism of PCDDs between Humans and Rats
3.8. Generation of 2,3,7,8-tetraCDD-Metabolizing CYPs by Modifying Rat CYP1A1 through Site-Directed Mutagenesis
4. Metabolism of PCBs by Human and Rat CYPs
4.1. In Vitro Metabolism of CB126 with Microsomal Fractions from Recombinant Yeast
4.2. Identification of CB126 Metabolites
4.3. Molecular Modeling of Human and Rat CYP1A1s
Rat | Human | Dog | Golden Hamster | Guinea Pig | Monkey | Mouse | Rabbit |
---|---|---|---|---|---|---|---|
| | | | | | | |
Ala | Ser | Thr | Thr | Ser | Ser | Thr | Thr |
| | | | | | | |
Tyr | Tyr | Tyr | Tyr | Ser | His | Tyr | Tyr |
| | | | | | | |
Phe | Leu | Leu | Val | Leu | Leu | Leu | Leu |
4.4. Construction of Docking Models with CB126 and CYP1A1s
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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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. https://doi.org/10.3390/ijms150814044
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. International Journal of Molecular Sciences. 2014; 15(8):14044-14057. https://doi.org/10.3390/ijms150814044
Chicago/Turabian StyleInui, Hideyuki, Toshimasa Itoh, Keiko Yamamoto, Shin-Ichi Ikushiro, and Toshiyuki Sakaki. 2014. "Mammalian Cytochrome P450-Dependent Metabolism of Polychlorinated Dibenzo-p-dioxins and Coplanar Polychlorinated Biphenyls" International Journal of Molecular Sciences 15, no. 8: 14044-14057. https://doi.org/10.3390/ijms150814044