Hydroxylation and dechlorination of 3,3',4,4'-tetrachlorobiphenyl (CB77) by rat and human CYP1A1s and critical roles of amino acids composing their substrate-binding cavity
Copyright © 2022 Elsevier B.V. All rights reserved..
Cytochrome P450 (CYP) monooxygenases play critical roles in determining the toxicity of polychlorinated biphenyls (PCBs) in mammals. Hydroxylation of PCBs by these enzymes leads to increased water solubility, promoting the elimination of PCBs from the body. The CYP1 family is mainly responsible for metabolizing PCBs that exhibit a dioxin-like toxicity. Although the dioxin-like PCB 3,3',4,4'-tetrachlorobiphenyl (CB77) is abundant in the environment and accumulates in organisms, information on CB77 metabolism by CYP1A1s is limited. In this study, recombinant rat CYP1A1 metabolized CB77 to 4'-hydroxy (OH)-3,3',4,5'-tetrachlorobiphenyl (CB79) and 4'-OH-3,3',4-trichlorobiphenyl (CB35), whereas human CYP1A1 produced only 4'-OH-CB79. Rat CYP1A1 exhibited much higher metabolizing activity than human CYP1A1 because CB77 was stably accommodated in the substrate-binding cavity of rat CYP1A1 and was close to its heme. In a rat CYP1A1 mutant with two human-type amino acids, the production of 4'-OH-CB79 decreased, whereas that of the dechlorinated metabolite 4'-OH-CB35 increased. These results are explained by a shift in the CB77 positions toward the heme. This study provides insight into the development of enzymes with high metabolizing activity and clarifies the structural basis of PCB metabolism, as dechlorination contributes to a drastic decrease in dioxin-like toxicity.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:837 |
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| Enthalten in: |
The Science of the total environment - 837(2022) vom: 01. Sept., Seite 155848 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yabu, Miku [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 10.06.2022 Date Revised 10.06.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.scitotenv.2022.155848 |
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| 245 | 1 | 0 | |a Hydroxylation and dechlorination of 3,3',4,4'-tetrachlorobiphenyl (CB77) by rat and human CYP1A1s and critical roles of amino acids composing their substrate-binding cavity |
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| 520 | |a Cytochrome P450 (CYP) monooxygenases play critical roles in determining the toxicity of polychlorinated biphenyls (PCBs) in mammals. Hydroxylation of PCBs by these enzymes leads to increased water solubility, promoting the elimination of PCBs from the body. The CYP1 family is mainly responsible for metabolizing PCBs that exhibit a dioxin-like toxicity. Although the dioxin-like PCB 3,3',4,4'-tetrachlorobiphenyl (CB77) is abundant in the environment and accumulates in organisms, information on CB77 metabolism by CYP1A1s is limited. In this study, recombinant rat CYP1A1 metabolized CB77 to 4'-hydroxy (OH)-3,3',4,5'-tetrachlorobiphenyl (CB79) and 4'-OH-3,3',4-trichlorobiphenyl (CB35), whereas human CYP1A1 produced only 4'-OH-CB79. Rat CYP1A1 exhibited much higher metabolizing activity than human CYP1A1 because CB77 was stably accommodated in the substrate-binding cavity of rat CYP1A1 and was close to its heme. In a rat CYP1A1 mutant with two human-type amino acids, the production of 4'-OH-CB79 decreased, whereas that of the dechlorinated metabolite 4'-OH-CB35 increased. These results are explained by a shift in the CB77 positions toward the heme. This study provides insight into the development of enzymes with high metabolizing activity and clarifies the structural basis of PCB metabolism, as dechlorination contributes to a drastic decrease in dioxin-like toxicity | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a 3,3′,4,4′-Tetrachlorobiphenyl | |
| 650 | 4 | |a Cytochrome P450 monooxygenase | |
| 650 | 4 | |a Dechlorination | |
| 650 | 4 | |a Dioxin-like polychlorinated biphenyl | |
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| 650 | 4 | |a Hydroxylation | |
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| 700 | 1 | |a Itoh, Toshimasa |e verfasserin |4 aut | |
| 700 | 1 | |a Goto, Erika |e verfasserin |4 aut | |
| 700 | 1 | |a Suzuki, Motoharu |e verfasserin |4 aut | |
| 700 | 1 | |a Yamazaki, Kiyoshi |e verfasserin |4 aut | |
| 700 | 1 | |a Mise, Shintaro |e verfasserin |4 aut | |
| 700 | 1 | |a Yamamoto, Keiko |e verfasserin |4 aut | |
| 700 | 1 | |a Matsumura, Chisato |e verfasserin |4 aut | |
| 700 | 1 | |a Nakano, Takeshi |e verfasserin |4 aut | |
| 700 | 1 | |a Sakaki, Toshiyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Inui, Hideyuki |e verfasserin |4 aut | |
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