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Research ArticleArticle

Epirubicin Glucuronidation Is Catalyzed by Human UDP-Glucuronosyltransferase 2B7

Federico Innocenti, Lalitha Iyer, Jacqueline Ramı́rez, Mitchell D. Green and Mark J. Ratain
Drug Metabolism and Disposition May 2001, 29 (5) 686-692;
Federico Innocenti
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Lalitha Iyer
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Jacqueline Ramı́rez
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Mitchell D. Green
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Mark J. Ratain
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Abstract

Epirubicin is one of the most active agents for breast cancer. The formation of epirubicin glucuronide by liver UDP-glucuronosyltransferase (UGT) is its main inactivating pathway. This study aimed to investigate epirubicin glucuronidation in human liver microsomes, to identify the specific UGT isoform for this reaction, and to correlate epirubicin glucuronidation with other UGT substrates. Microsomes from human livers were used. UGTs specifically expressed in cellular systems, as well as two UGT2B7 variants, were screened for epirubicin glucuronidation. Epirubicin, morphine, and SN-38 glucuronides were measured by high-pressure liquid chromatography. The mean ± S.D. formation rate of epirubicin glucuronide in human liver microsomes (n = 47) was 138 ± 37 pmol/min/mg (coefficient of variation, 24%). This phenotype was normally distributed. We screened commercially available UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 for epirubicin glucuronidation. Only UGT2B7 converted epirubicin to its glucuronide. No differences in epirubicin glucuronidation were found in HK293 cells expressing the two UGT2B7 variants at position 268. Catalytic efficiency (Vmax/Km) of epirubicin glucuronidation was 1.4 μl/min/mg, a value higher than that observed for morphine, a substrate of UGT2B7. Formation of epirubicin glucuronide was significantly related to that of morphine-3-glucuronide (r = 0.76, p< 0.001) and morphine-6-glucuronide (r = 0.73,p < 0.001). No correlation was found with SN-38, a substrate of UGT1A1 (r = 0.04). UGT2B7 is the major human UGT catalyzing epirubicin glucuronidation, andUGT2B7 is the candidate gene for this phenotype. The reported tyrosine to histidine polymorphism in UGT2B7 does not alter the formation rate of epirubicin glucuronide, and undiscovered genetic polymorphisms in UGT2B7 might change the metabolic fate of this important anticancer agent.

Footnotes

  • Send reprint requests to: Mark J. Ratain, M.D., The University of Chicago, 5841 South Maryland Ave., MC 2115, Chicago, IL 60637. E-mail: mratain{at}medicine.bsd.uchicago.edu

  • This Pharmacogenetics of Anticancer Agents Research Group study was supported in part by Grant GM61393 from the National Institutes of Health, Bethesda, MD, and Grant 106089/14/97/03566 from National Research Council (CNR), Rome, Italy. The primary data will be deposited into PharmGKB, supported by grants from the National Institute of General Medical Sciences (NIGMS), Human Genome Research Institute (NHGRI), and National Library of Medicine (NLM) within the National Institutes of Health (NIH) and the Pharmacogenetics Research Network.

  • Abbreviations used are::
    UGT
    UDP-glucuronosyltransferase
    AUC
    area under the concentration-time curve
    cDNA
    complementary DNA
    CN-I
    Crigler-Najjar syndrome type I
    ECOD
    7-ethoxycoumarin O-deethylation
    HPLC
    high-pressure liquid chromatography
    Tris
    tris(hydroxymethyl)aminomethane
    UDPGA
    UDP-glucuronic acid
    M3G
    morphine-3-glucuronide
    M6G
    morphine-6-glucuronide
    • Received November 16, 2000.
    • Accepted January 30, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (5)
Drug Metabolism and Disposition
Vol. 29, Issue 5
1 May 2001
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Research ArticleArticle

Epirubicin Glucuronidation Is Catalyzed by Human UDP-Glucuronosyltransferase 2B7

Federico Innocenti, Lalitha Iyer, Jacqueline Ramı́rez, Mitchell D. Green and Mark J. Ratain
Drug Metabolism and Disposition May 1, 2001, 29 (5) 686-692;

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Research ArticleArticle

Epirubicin Glucuronidation Is Catalyzed by Human UDP-Glucuronosyltransferase 2B7

Federico Innocenti, Lalitha Iyer, Jacqueline Ramı́rez, Mitchell D. Green and Mark J. Ratain
Drug Metabolism and Disposition May 1, 2001, 29 (5) 686-692;
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