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Research ArticleArticle

Metabolism of the Endocrine Disruptor Pesticide-Methoxychlor by Human P450s: Pathways Involving a Novel Catechol Metabolite

Yiding Hu and David Kupfer
Drug Metabolism and Disposition September 2002, 30 (9) 1035-1042; DOI: https://doi.org/10.1124/dmd.30.9.1035
Yiding Hu
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Abstract

The metabolism of methoxychlor, a proestrogenic pesticide (endocrine disruptor), was investigated with cDNA expressed human cytochrome P450s and liver microsomes (HLM). In addition to 1,1,1-trichloro-2-(4-hydroxyphenyl)-2-(4-methoxyphenyl)ethane (mono-OH-M), 1,1,1-trichloro-2, 2-bis(4-hydroxyphenyl)ethane (bis-OH-M), and 1,1,1-trichloro-2-(4-hydroxyphenyl)-2-(3, 4-dihydroxyphenyl)ethane (tris-OH-M), a new metabolite was identified as 1,1,1-trichloro-2-(4-methoxyphenyl)-2-(3, 4-dihydroxyphenyl)ethane (catechol-M; previously assumed to be ring-OH-M) and as a key metabolic intermediate. A novel metabolic route was proposed involving methoxychlor O-demethylation to mono-OH-M, followed by bifurcation of the pathway, both leading to the same final product tris-OH-M: pathway a, mono-OH-M is demethylated to bis-OH-M, followed by ortho-hydroxylation forming tris-OH-M and pathway b, mono-OH-M is ortho-hydroxylated forming catechol-M that isO-demethylated forming tris-OH-M. Among the human cDNA-expressed P450s examined, CYP1A2, 2A6, 2C8, 2C9, 2C19, and 2D6 exhibited mainly O-demethylation, with CYP2C19 being the most catalytically competent. CYP3A4, 3A5, and rat 2B1 catalyzed primarily ortho-hydroxylation of mono-OH-M (CYP3A4 being catalytically the most active) but were weak inO-demethylation. CYP1A1, 1B1, 2E1, and 4A11 demonstrated little or no catalytic activity. CYP2B6 appeared unique, catalyzing effectively both O-demethylation andortho-hydroxylation. Thus, CYP2B6 demethylated methoxychlor to mono-OH-M and ortho-hydroxylated the mono-OH-M forming catechol-M; however, 2B6 did not appreciably demethylate mono-OH-M orortho-hydroxylate bis-OH-M, suggesting a narrow substrate specificity. CYP2C19-catalyzed demethylation of methoxychlor, mono-OH-M and catechol-M, demonstrating relatively good substrate affinity (Km = 0.23 − 0.41 μM). However, the 3A4 ortho-hydroxylation of mono-OH-M and bis-OH-M exhibited lower affinity,Km = 12 and 25 μM, respectively. Thus, a phenolic group seems essential for efficientortho-hydroxylation, forming catechol-M and tris-OH-M. Inhibition studies with HLM and P450s indicate that CYP2C9 and likely 2C19 are catalysts of methoxychlor-mono-demethylation.

Footnotes

  • The project described was supported by an National Institutes of Health Grant ES00834 from the National Institute of Environmental Health Sciences (NIEHS) and its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIEHS.

  • Abbreviations used are::
    methoxychlor
    1,1,1-trichloro-2, 2-bis(4-methoxyphenyl)ethane
    ER
    estrogen receptor
    mono-OH-M
    1,1,1-trichloro-2-(4-hydroxyphenyl)-2-(4-methoxyphenyl)ethane
    bis-OH-M
    1,1,1-trichloro-2, 2-bis(4-hydroxyphenyl)ethane
    catechol-M
    1,1,1-trichloro-2-(4-methoxyphenyl)-2-(3, 4-dihydroxyphenyl)ethane
    tris-OH-M
    1,1,1-trichloro-2-(4-hydroxyphenyl)-2-(3, 4-dihydroxyphenyl)ethane
    tetra-OH-M
    1,1,1-trichloro-2, 2-bis-(3, 4-dihydroxyphenyl)ethane
    ring-OH-M
    1,1,1-trichloro-2-(4-methoxyphenyl)-2-(3-hydroxy-4-methoxyphenyl)ethane
    ring-OMe-mono-OH-M (ring-methoxy-mono-OH-M)
    1,1,1-trichloro-2-(4-methoxyphenyl)-2-(3-methoxy-4-hydroxyphenyl)ethane
    tris-OMe-M (tris-methoxy-M)
    1,1,1-trichloro-2-(4-methoxyphenyl)-2-(3,4-dimethoxyphenyl)ethane
    P450
    cytochrome P450
    HPLC
    high-performance liquid chromatography
    TLC
    thin layer chromatography
    HLM
    human liver microsomes
    • Received April 4, 2002.
    • Accepted June 11, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (9)
Drug Metabolism and Disposition
Vol. 30, Issue 9
1 Sep 2002
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Research ArticleArticle

Metabolism of the Endocrine Disruptor Pesticide-Methoxychlor by Human P450s: Pathways Involving a Novel Catechol Metabolite

Yiding Hu and David Kupfer
Drug Metabolism and Disposition September 1, 2002, 30 (9) 1035-1042; DOI: https://doi.org/10.1124/dmd.30.9.1035

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Research ArticleArticle

Metabolism of the Endocrine Disruptor Pesticide-Methoxychlor by Human P450s: Pathways Involving a Novel Catechol Metabolite

Yiding Hu and David Kupfer
Drug Metabolism and Disposition September 1, 2002, 30 (9) 1035-1042; DOI: https://doi.org/10.1124/dmd.30.9.1035
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