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Research ArticleArticle

UDP-GLUCURONOSYLTRANSFERASE ISOFORMS CATALYZING GLUCURONIDATION OF HYDROXY-POLYCHLORINATED BIPHENYLS IN RAT

Tomo Daidoji, Keisuke Gozu, Hidetomo Iwano, Hiroki Inoue and Hiroshi Yokota
Drug Metabolism and Disposition October 2005, 33 (10) 1466-1476; DOI: https://doi.org/10.1124/dmd.105.004416
Tomo Daidoji
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Keisuke Gozu
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Hidetomo Iwano
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Hiroki Inoue
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Hiroshi Yokota
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Abstract

Polychlorinated biphenyls (PCBs) are highly toxic environmental contaminants that can cause irreversible damage in humans and wildlife. The mechanism of toxicity is not clear, but biotransformation products such as hydroxy PCBs (OH-PCBs) are a major concern. Efforts to elucidate the metabolism of PCBs and their metabolites, however, have paid little attention to the structure of the compound to be eliminated. The objectives of this study were to clarify organ tissue distribution of the glucuronidation activities toward OH-PCBs and to determine the UDP-glucuronosyltranseferase (UGT) isoforms responsible for glucuronidation in relation to the OH-PCB structure. 2,4,6-Trichlorobiphenyl and 2,3,4,5-tetrachlorobiphenyl were incubated in primary culture of rat hepatocytes, and the metabolites were identified by HPLC. Organ tissue glucuronidation activities toward 10 OH-PCBs were investigated by reactions of microsomes prepared from brain, liver, small and large intestine, lung, kidney, and testis tissues. To determine substrate specificity of the isoforms toward the OH-PCBs, rat UGT isoforms UGT1A1, UGT1A3, UGT1A5, UGT1A6, UGT1A7, UGT2B1, UGT2B3, and UGT2B12 were expressed in yeast strain AH22. Glucuronidation of the PCBs was found to be contingent on their hydroxylation. The organ tissues had strong glucuronidation activities toward the OH-PCBs tested; and most OH-PCBs were glucuronidated by UGT1A1, UGT1A6, and UGT2B1, all of which were substrate-specific. In conclusion, glucuronidation activities of UGT1A1, UGT1A6, and UGT2B1 toward OH-PCBs is relative to expression of the isoforms in each tissue, and glucuronidation intensity of the isoforms is relative to the structure of the OH-PCB to be glucuronidated.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.105.004416.

  • ABBREVIATIONS: PCB, polychlorinated biphenyl; OH-PCB, hydroxy-polychlorinated biphenyl; UGT, UDP-glucuronosyltransferase; PCB30, 2,4,6-trichlorobiphenyl; PCB61, 2,3,4,5-tetrachlorobiphenyl; HPLC, high-performance liquid chromatography; 4-OH-PCB30, 4-hydroxy-PCB30; 4-OH-PCB61, 4-hydroxy-PCB61; RT-PCR, reverse transcription-polymerase chain reaction; bp, base pair(s); 4-OH-PCB109, 2,3,3′,4′,5-penta CB; 4-OH-PCB146, 2,2′,3,4′,5,5′-hexa CB; 4-OH-PCB187, 2,2′,3,4′,5,5′,6-hepta CB; hEST, human estrogen sulfotransferase.

  • ↵ Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

    • Received February 25, 2005.
    • Accepted June 29, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (10)
Drug Metabolism and Disposition
Vol. 33, Issue 10
1 Oct 2005
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Research ArticleArticle

UDP-GLUCURONOSYLTRANSFERASE ISOFORMS CATALYZING GLUCURONIDATION OF HYDROXY-POLYCHLORINATED BIPHENYLS IN RAT

Tomo Daidoji, Keisuke Gozu, Hidetomo Iwano, Hiroki Inoue and Hiroshi Yokota
Drug Metabolism and Disposition October 1, 2005, 33 (10) 1466-1476; DOI: https://doi.org/10.1124/dmd.105.004416

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Research ArticleArticle

UDP-GLUCURONOSYLTRANSFERASE ISOFORMS CATALYZING GLUCURONIDATION OF HYDROXY-POLYCHLORINATED BIPHENYLS IN RAT

Tomo Daidoji, Keisuke Gozu, Hidetomo Iwano, Hiroki Inoue and Hiroshi Yokota
Drug Metabolism and Disposition October 1, 2005, 33 (10) 1466-1476; DOI: https://doi.org/10.1124/dmd.105.004416
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