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Research ArticleArticle

O-Glucuronidation of the Lung Carcinogen 4-(methylnitrosamino)-1- (3-Pyridyl)-1-Butanol (nnal) by Human Udp-Glucuronosyltransferases 2b7 and 1a9

Qing Ren, Sharon E. Murphy, Zhong Zheng and Philip Lazarus
Drug Metabolism and Disposition November 2000, 28 (11) 1352-1360;
Qing Ren
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Sharon E. Murphy
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Zhong Zheng
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Philip Lazarus
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Abstract

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone and its major metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), are potent lung carcinogens in animals. UGT-mediatedO-glucuronidation of NNAL is an important detoxification pathway for these carcinogens. To better characterize this pathway in humans, we screened a series of UGT-overexpressing cell lines and baculosome preparations for their ability toO-glucuronidate NNAL and examined multiple human liver and lung specimens for NNAL-glucuronidating activity and their levels of expression of NNAL-glucuronidating UGTs. Human liver microsomal fractions exhibited significant levels of NNAL-glucuronidating activity, with the NNAL-Gluc II diastereomer formed at a rate 3.4 times that observed for NNAL-Gluc I. As with liver microsomal fractions, NNAL-Gluc II was the major diastereomer formed by homogenates from UGT2B7-overexpressing HK293 cells or UGT2B7-overexpressing baculosomes; the major diastereomer formed by homogenates from UGT1A9-overexpressing V79 cells was NNAL-Gluc I. No significantO-glucuronidating activity of NNAL was detected in UGT1A1-, UGT1A4-, UGT1A6-, UGT2B4-, or UGT2B15-overexpressing HK293 or V79 cell homogenates, or in UGT1A1-, UGT1A3-, UGT1A7-, or UGT1A10-overexpressing baculosomes. Significant levels of UGT2B7 mRNA were detected by reverse transcriptase-polymerase chain reaction in human liver and at low levels in human lung specimens. UGT1A9 mRNA was detected in liver but not in lung. These results suggest that although both UGT2B7 and UGT1A9 play an important role in the overall glucuronidation of NNAL in humans, UGT2B7 potentially plays an important role in the detoxification of NNAL in the lung.

Footnotes

  • Send reprint requests to: Philip Lazarus, Ph.D., Divisions of Cancer Control and Molecular Oncology, H. Lee Moffitt Cancer Center, University of South Florida, MRC-2E, 12902 Magnolia Dr., Tampa, FL. E-mail: plazarus{at}moffitt.usf.edu

  • This research was supported by National Institutes of Health Grants CA52216 (to P.L.) and DE12206 (to P.L.). This research was presented at the American Association for Cancer Research Meeting, 2000, in San Francisco, CA. [Ren et al. (2000) Proc Am Assoc Cancer Res 41:5336.]

  • Abbreviations used are::
    NNK
    4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
    NNAL
    4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol
    UGT
    UDP-glucuronosyltransferase
    NNAL-Gluc
    β-O-[4-(methylnitrosamino)-1-(3-pyridyl)-1-but-1-yl]-d-glucosiduronic acid
    UDPGA
    UDP-glucuronic acid
    4-NP
    4-nitrophenol
    TLC
    thin layer chromatography
    RT
    reverse transcriptase
    PCR
    polymerase chain reaction
    • Received June 15, 2000.
    • Accepted August 14, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (11)
Drug Metabolism and Disposition
Vol. 28, Issue 11
1 Nov 2000
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Research ArticleArticle

O-Glucuronidation of the Lung Carcinogen 4-(methylnitrosamino)-1- (3-Pyridyl)-1-Butanol (nnal) by Human Udp-Glucuronosyltransferases 2b7 and 1a9

Qing Ren, Sharon E. Murphy, Zhong Zheng and Philip Lazarus
Drug Metabolism and Disposition November 1, 2000, 28 (11) 1352-1360;

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Research ArticleArticle

O-Glucuronidation of the Lung Carcinogen 4-(methylnitrosamino)-1- (3-Pyridyl)-1-Butanol (nnal) by Human Udp-Glucuronosyltransferases 2b7 and 1a9

Qing Ren, Sharon E. Murphy, Zhong Zheng and Philip Lazarus
Drug Metabolism and Disposition November 1, 2000, 28 (11) 1352-1360;
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