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Hepatic Cytochrome P450 Enzyme Alterations in Humans with Progressive Stages of Nonalcoholic Fatty Liver Disease

Craig D. Fisher, Andrew J. Lickteig, Lisa M. Augustine, James Ranger-Moore, Jonathan P. Jackson, Stephen S. Ferguson and Nathan J. Cherrington
Drug Metabolism and Disposition October 2009, 37 (10) 2087-2094; DOI: https://doi.org/10.1124/dmd.109.027466
Craig D. Fisher
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Andrew J. Lickteig
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Lisa M. Augustine
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James Ranger-Moore
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Jonathan P. Jackson
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Stephen S. Ferguson
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Nathan J. Cherrington
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Abstract

Members of the cytochrome P450 (P450) enzyme families CYP1, CYP2, and CYP3 are responsible for the metabolism of approximately 75% of all clinically relevant drugs. With the increased prevalence of nonalcoholic fatty liver disease (NAFLD), it is likely that patients with this disease represent an emerging population at significant risk for alterations in these important drug-metabolizing enzymes. The purpose of this study was to determine whether three progressive stages of human NALFD alter hepatic P450 expression and activity. Microsomes isolated from human liver samples diagnosed as normal, n = 20; steatosis, n = 11; nonalcoholic steatohepatitis (NASH) (fatty liver), n = 10; and NASH (no longer fatty), n = 11 were analyzed for P450 mRNA, protein, and enzyme activity. Microsomal CYP1A2, CYP2D6, and CYP2E1 mRNA levels were decreased with NAFLD progression, whereas CYP2A6, CYP2B6, and CYP2C9 mRNA expression increased. Microsomal protein expression of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 tended to decrease with NAFLD progression. Likewise, functional activity assays revealed decreasing trends in CYP1A2 (p = 0.001) and CYP2C19 (p = 0.05) enzymatic activity with increasing NAFLD severity. In contrast, activity of CYP2A6 (p = 0.001) and CYP2C9 (diclofenac, p = 0.0001; tolbutamide, p = 0.004) was significantly increased with NAFLD progression. Increased expression of proinflammatory cytokines tumor necrosis factor α and interleukin 1β was observed and may be responsible for observed decreases in respective P450 activity. Furthermore, elevated CYP2C9 activity during NAFLD progression correlated with elevated hypoxia-induced factor 1α expression in the later stages of NAFLD. These results suggest that significant and novel changes occur in hepatic P450 activity during progressive stages of NAFLD.

  • P450, cytochrome P450
  • NAFLD, nonalcoholic fatty liver disease
  • NASH, nonalcoholic steatohepatitis
  • GAPDH, glyceraldehyde-3-phosphate dehydrogenase
  • CT, threshold cycle
  • IL-1β, interleukin 1β
  • TNFα, tumor necrosis factor α
  • HIF-1α, hypoxia-induced factor 1α.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute of Environmental Health Sciences [Grant ES007091]; the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK068039]; and the National Institutes of Health National Center for Complementary and Alternative Medicine [Grant AT002842]. The Liver Tissue Cell Distribution System was sponsored by the National Institutes of Health [Contract N01-DK-7-0004/HHSN267200700004C].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

    • Received March 22, 2009.
    • Accepted July 27, 2009.
  • Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (10)
Drug Metabolism and Disposition
Vol. 37, Issue 10
October 2009
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Hepatic Cytochrome P450 Enzyme Alterations in Humans with Progressive Stages of Nonalcoholic Fatty Liver Disease

Craig D. Fisher, Andrew J. Lickteig, Lisa M. Augustine, James Ranger-Moore, Jonathan P. Jackson, Stephen S. Ferguson and Nathan J. Cherrington
Drug Metabolism and Disposition October 1, 2009, 37 (10) 2087-2094; DOI: https://doi.org/10.1124/dmd.109.027466

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Hepatic Cytochrome P450 Enzyme Alterations in Humans with Progressive Stages of Nonalcoholic Fatty Liver Disease

Craig D. Fisher, Andrew J. Lickteig, Lisa M. Augustine, James Ranger-Moore, Jonathan P. Jackson, Stephen S. Ferguson and Nathan J. Cherrington
Drug Metabolism and Disposition October 1, 2009, 37 (10) 2087-2094; DOI: https://doi.org/10.1124/dmd.109.027466
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