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Research ArticleArticle

Reductive Metabolism ofp,p′-DDT ando,p′-DDT by Rat Liver Cytochrome P450

Shigeyuki Kitamura, Yuri Shimizu, Yuko Shiraga, Mayumi Yoshida, Kazumi Sugihara and Shigeru Ohta
Drug Metabolism and Disposition February 2002, 30 (2) 113-118; DOI: https://doi.org/10.1124/dmd.30.2.113
Shigeyuki Kitamura
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Yuri Shimizu
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Yuko Shiraga
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Mayumi Yoshida
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Kazumi Sugihara
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Shigeru Ohta
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Abstract

The in vitro metabolism of p,p′-DDT [1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane], an important environmental pollutant, was examined in rat liver, focusing on reductive dechlorination. When p,p′-DDT was incubated with liver microsomes of rats in the presence of NADPH or NADH, a dechlorinated metabolite,p,p′-DDD [1,1-dichloro-2,2-bis(4-chlorophenyl)ethane], was formed under anaerobic conditions together with a dehydrochlorinated metabolite,p,p′-DDE [1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene].p,p′-DDE was also formed fromp,p′-DDD by liver microsomes. The dechlorinating activity was inhibited by carbon monoxide, metyrapone, and SKF 525-A (proadifen hydrochloride), but the dehydrochlorinating activity was unaffected. The reductase activity toward p,p′-DDT was induced by the pretreatment of rats with phenobarbital and dexamethasone. The dechlorination was catalyzed enzymatically by recombinant cytochrome P450 2B1, 3A1, 2B6, and 3A4. Whenp,p′-DDT was incubated with liver microsomes of rats in the presence of both a reduced pyridine nucleotide and FMN, p,p′-DDD was also formed under anaerobic conditions. In this case, the dechlorinating activity was not abolished when the microsomes were boiled. The reductase activities were inhibited by carbon monoxide. Hematin exhibited reductase activity towardp,p′-DDT in the presence of NADH and FMN. The activity of hematin was also supported by FMNH2. The reductive dechlorination also seems to proceed nonenzymatically with the reduced flavin, catalyzed by the heme group of cytochrome P450. Similar enzymatic and nonenzymatic reducing activities were observed toward o,p′-DDT [1,1,1-trichloro-2,2-bis(2-chlorophenyl-4-chlorophenyl)ethane].

Footnotes

  • This work was supported by Grant-in-Aid 13027256 for Scientific Research on Priority Area from the Japanese Ministry of Education, Science, Sports, and Culture and Grant-in-Aid C13672343 for Scientific Research from the Japan Society for the Promotion of Science.

  • Abbreviations used are::
    CYP
    cytochrome P450
    p,p′-DDE
    1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene
    p,p′-DDD
    1,1-dichloro-2,2-bis(4-chlorophenyl)ethane
    p,p′-DDA
    2,2-bis(4-chlorophenyl)acetic acid
    p,p′-DDMU
    1-chloro-2,2-bis(4-chlorophenyl)ethylene
    HPLC
    high-performance liquid chromatography
    TLC
    thin-layer chromatography
    SKF 525-A
    proadifen hydrochloride
    • Received July 9, 2001.
    • Accepted October 18, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (2)
Drug Metabolism and Disposition
Vol. 30, Issue 2
1 Feb 2002
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Research ArticleArticle

Reductive Metabolism ofp,p′-DDT ando,p′-DDT by Rat Liver Cytochrome P450

Shigeyuki Kitamura, Yuri Shimizu, Yuko Shiraga, Mayumi Yoshida, Kazumi Sugihara and Shigeru Ohta
Drug Metabolism and Disposition February 1, 2002, 30 (2) 113-118; DOI: https://doi.org/10.1124/dmd.30.2.113

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Research ArticleArticle

Reductive Metabolism ofp,p′-DDT ando,p′-DDT by Rat Liver Cytochrome P450

Shigeyuki Kitamura, Yuri Shimizu, Yuko Shiraga, Mayumi Yoshida, Kazumi Sugihara and Shigeru Ohta
Drug Metabolism and Disposition February 1, 2002, 30 (2) 113-118; DOI: https://doi.org/10.1124/dmd.30.2.113
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