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Research ArticleArticle

SHORT-TERM INHIBITORY EFFECTS OF NITRIC OXIDE ON CYTOCHROME P450-MEDIATED DRUG METABOLISM: TIME DEPENDENCY AND REVERSIBILITY PROFILES IN ISOLATED PERFUSED RAT LIVERS

Ragini Vuppugalla and Reza Mehvar
Drug Metabolism and Disposition December 2004, 32 (12) 1446-1454; DOI: https://doi.org/10.1124/dmd.104.001487
Ragini Vuppugalla
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Reza Mehvar
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Abstract

Nitric oxide (NO) is implicated as a mediator in the decreased catalytic activities of cytochrome P450 (P450) enzymes during inflammation or infection. Here, we examined the time course and the reversibility of the NO effect on P450s using isolated perfused rat livers. Livers were perfused at a constant rate with the NO donor sodium nitroprusside (SNP) for 0.5 or 1 h, followed by washout periods of 0 to 2.5 h. At the end of perfusion, microsomes were prepared and analyzed for P450 activities and other metabolic markers. Whereas 0.5 h of NO exposure caused an irreversible decline (∼30%) in total P450 content, a greater decline after 1 h of NO (∼55%) was mostly (∼30%) reversible, a pattern identical to that observed for the microsomal heme content. NO exposure also caused an enzyme-selective and time-dependent decline in P450 activities. Whereas the pattern of decline and reversibility of activities were qualitatively similar for CYP3A2, 2C11, 2E1, and 1A1/2, they differed for 2B1/2 and 2D1 in that the decline in the activity was delayed (1 h) for 2B1/2 and not observed for 2D1. This may be attributed to the accessibility of heme or cysteine thiolate and/or the presence/reactivity of critical cysteinyl amino acid residues in various P450 enzymes. Additionally, for most enzymes, the activity showed a biphasic decline, one within 1 h of SNP perfusion and another after 2 h of washout. This was associated with an identical biphasic decline in the microsomal free thiols, presumably due to the rapid and slow reaction of NO and peroxynitrite, respectively, with critical P450 thiols. The short-term effects of NO on P450 are time-dependent and enzyme-selective, with both reversible and irreversible mechanisms.

Footnotes

  • doi:10.1124/dmd.104.001487.

  • ABBREVIATIONS: P450, cytochrome P450; LPS, lipopolysaccharide(s); NO, nitric oxide; NOS, nitric-oxide synthase; IPRL, isolated perfused rat liver; SNP, sodium nitroprusside; NOx, nitrate/nitrite; DTT, dithiotreitol; Vmax, maximum velocity of metabolism; Km, Michaelis-Menten constant.

    • Received July 15, 2004.
    • Accepted September 14, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 32 (12)
Drug Metabolism and Disposition
Vol. 32, Issue 12
1 Dec 2004
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SHORT-TERM INHIBITORY EFFECTS OF NITRIC OXIDE ON CYTOCHROME P450-MEDIATED DRUG METABOLISM: TIME DEPENDENCY AND REVERSIBILITY PROFILES IN ISOLATED PERFUSED RAT LIVERS
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Research ArticleArticle

SHORT-TERM INHIBITORY EFFECTS OF NITRIC OXIDE ON CYTOCHROME P450-MEDIATED DRUG METABOLISM: TIME DEPENDENCY AND REVERSIBILITY PROFILES IN ISOLATED PERFUSED RAT LIVERS

Ragini Vuppugalla and Reza Mehvar
Drug Metabolism and Disposition December 1, 2004, 32 (12) 1446-1454; DOI: https://doi.org/10.1124/dmd.104.001487

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Research ArticleArticle

SHORT-TERM INHIBITORY EFFECTS OF NITRIC OXIDE ON CYTOCHROME P450-MEDIATED DRUG METABOLISM: TIME DEPENDENCY AND REVERSIBILITY PROFILES IN ISOLATED PERFUSED RAT LIVERS

Ragini Vuppugalla and Reza Mehvar
Drug Metabolism and Disposition December 1, 2004, 32 (12) 1446-1454; DOI: https://doi.org/10.1124/dmd.104.001487
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