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Research ArticleArticle

Involvement of Human Cytochrome P450 2D6 in the Bioactivation of Acetaminophen

Haijun Dong, Robert L. Haining, Kenneth E. Thummel, Allan E. Rettie and Sidney D. Nelson
Drug Metabolism and Disposition December 2000, 28 (12) 1397-1400;
Haijun Dong
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Robert L. Haining
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Kenneth E. Thummel
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Allan E. Rettie
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Sidney D. Nelson
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Abstract

Acetaminophen (APAP), a widely used analgesic and antipyretic agent, can cause acute hepatic necrosis in both humans and experimental animals when consumed in large doses. It is generally accepted thatN-acetyl-p-benzoquinone imine (NAPQI) is the toxic, reactive intermediate whose formation from APAP is mediated by cytochrome P450. Several forms of P450 in humans, including 2E1, 1A2, 2A6, 3A4, have been shown to catalyze the oxidation of APAP to NAPQI. We now present evidence which demonstrates that human cytochrome P450 2D6 (CYP2D6) is also involved in the bioactivation of APAP. The formation of NAPQI from APAP by cDNA-expressed CYP2D6 was examined.Km and Vmaxvalues were 1.76 mM and 3.02 nmol/min/nmol of P450, respectively, such that the efficiency of CYP2D6 in the conversion of APAP to NAPQI is approximately one-third of that of CYP2E1. The contribution of CYP2D6 to the total formation of NAPQI from APAP (1 mM) in human liver was investigated using quinidine (1 μm) as a CYP2D6-specific inhibitor, and varied from 4.5 to 22.4% among 10 livers, with an average at 12.6%. The correlation between the contribution of CYP2D6 to NAPQI formation in human liver microsomes and the CYP2D6 activity probed by the O-demethylation of dextromethorphan was studied, and found to be strong (r2 = 0.85), and significant (P < .0001). Our findings indicate that CYP2D6, one of the major P450 isoforms in humans and also one of the pharmacogenetically important isoforms, may contribute significantly to the formation of the cytotoxic metabolite NAPQI, especially in CYP2D6 ultra-rapid and extensive metabolizers and at toxic doses of APAP when plasma APAP concentrations reach 2 mM or more.

Footnotes

  • Send reprint requests to: Sidney D. Nelson, Ph.D., Department of Medicinal Chemistry, School of Pharmacy, Box 357610, University of Washington, Seattle, WA 98195-7610. E-mail:sidnels{at}u.washington.edu

  • This research was financially supported by National Institutes of Health Grants GM32165, ES07033 (S.D.N.) and ES09894 (R.L.H.).

  • ↵2 The formation of the nontoxic catechol metabolite, 3-OH-APAP, was not measurable, and related kinetic parameters were not determined.

  • Abbreviations used are::
    APAP
    acetaminophen
    CYP
    cytochrome P450
    DLPC
    dilauroyll-α-phosphatidylcholine
    GSH
    glutathione
    NAPQI
    N-acetyl-p-benzoquinone imine
    3-OH-APAP
    3-hydroxy-APAP
    GS-APAP
    3′-glutathion-S-yl-APAP
    • Received April 11, 2000.
    • Accepted September 5, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (12)
Drug Metabolism and Disposition
Vol. 28, Issue 12
1 Dec 2000
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Research ArticleArticle

Involvement of Human Cytochrome P450 2D6 in the Bioactivation of Acetaminophen

Haijun Dong, Robert L. Haining, Kenneth E. Thummel, Allan E. Rettie and Sidney D. Nelson
Drug Metabolism and Disposition December 1, 2000, 28 (12) 1397-1400;

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Research ArticleArticle

Involvement of Human Cytochrome P450 2D6 in the Bioactivation of Acetaminophen

Haijun Dong, Robert L. Haining, Kenneth E. Thummel, Allan E. Rettie and Sidney D. Nelson
Drug Metabolism and Disposition December 1, 2000, 28 (12) 1397-1400;
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