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Research ArticleArticle

Immunoquantitation of FMO1 in Human Liver, Kidney, and Intestine

Catherine K. Yeung, Dieter H. Lang, Kenneth E. Thummel and Allan E. Rettie
Drug Metabolism and Disposition September 2000, 28 (9) 1107-1111;
Catherine K. Yeung
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Dieter H. Lang
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Kenneth E. Thummel
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Allan E. Rettie
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Abstract

To determine the level of FMO1 protein present in human liver tissues, a monospecific antibody was prepared and a sensitive Western blotting procedure with enhanced chemiluminescence detection was developed. Human FMO1, purified from insect cells expressing the recombinant protein, was used as a protein standard for absolute quantification. The average concentrations of FMO1 in microsomes prepared from human liver, kidney, intestine, and fetal liver were found to be <1, 47 ± 9, 2.9 ± 1.9, and 14.4 ± 3.5 pmol/mg, respectively. Quantitation in intestinal microsomes was complicated by variable degrees of proteolytic degradation of FMO1, not seen in microsomes prepared from liver or kidney. Recombinant human FMO1 and detergent-solubilized human duodenal microsomes both metabolized p-tolyl methyl sulfide stereoselectively to the (R)-sulfoxide, indicating the expression of functional FMO1 in human intestine. The relatively high levels of immunoquantifiable FMO1 in human kidney and fetal liver complement our previous catalytic studies in these tissues, which also demonstrated preferential (R)-p-tolyl methyl sulfoxide formation. These data demonstrate a profound ontogenic change in expression of hepatic FMO1 in humans, such that in adult life FMO1 is exclusively an extrahepatic drug-metabolizing enzyme. The marked expression levels of FMO1 found in human kidney coupled to the high catalytic activity of this isoform toward a diverse array of sulfides and tertiary amines suggest the possibility that human renal FMO1 is a significant contributor to the metabolic clearance of drugs and other xenobiotics bearing these functionalities.

Footnotes

  • Send reprint requests to: Allan E. Rettie, Department of Medicinal Chemistry, University of Washington, Box 357610, Seattle WA 98195. E-mail: rettie{at}u.washington.edu

  • ↵1 Current address: Bayer AG, D-42096 Wuppertal, Germany.

  • This work was supported by National Institutes of Health Grant GM43511. C.K.Y. was supported by NIH Training Grant GM07750.

  • Abbreviations used are::
    FMO
    flavin-containing monooxygenases
    PAGE
    polyacrylamide gel electrophoresis
    BCIP/NBT
    5-bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium
    HL
    human adult liver
    HK
    human adult kidney
    HI
    human adult intestine
    FL
    fetal liver
    CYP
    cytochrome P-450
    ECL
    enhanced chemiluminescence
    • Received March 29, 2000.
    • Accepted June 12, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (9)
Drug Metabolism and Disposition
Vol. 28, Issue 9
1 Sep 2000
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Research ArticleArticle

Immunoquantitation of FMO1 in Human Liver, Kidney, and Intestine

Catherine K. Yeung, Dieter H. Lang, Kenneth E. Thummel and Allan E. Rettie
Drug Metabolism and Disposition September 1, 2000, 28 (9) 1107-1111;

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Research ArticleArticle

Immunoquantitation of FMO1 in Human Liver, Kidney, and Intestine

Catherine K. Yeung, Dieter H. Lang, Kenneth E. Thummel and Allan E. Rettie
Drug Metabolism and Disposition September 1, 2000, 28 (9) 1107-1111;
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