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Research ArticleArticle

ENZYME-SELECTIVE EFFECTS OF NITRIC OXIDE ON AFFINITY AND MAXIMUM VELOCITY OF VARIOUS RAT CYTOCHROMES P450

Ragini Vuppugalla and Reza Mehvar
Drug Metabolism and Disposition June 2005, 33 (6) 829-836; DOI: https://doi.org/10.1124/dmd.105.003848
Ragini Vuppugalla
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Reza Mehvar
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Abstract

Nitric oxide (NO) has recently been shown to decrease cytochrome P450 (P450) enzyme activity rapidly (≤30 min), concentration dependently, and enzyme-selectively in the rat liver. Interestingly, among all the studied P450 enzymes, only CYP2D1 was not affected by NO donors. However, these studies were conducted using only a single concentration of the substrates, thus lacking information about the possible simultaneous changes in both maximum velocity (Vmax) and affinity (Km) of the enzymes. In the present study, we systematically evaluated the effects of NO on the enzyme kinetic parameters of marker substrates for a range of P450 enzymes, including 2D1. Livers were perfused (1 h) in the absence (control) or presence of two NO donors with different mechanisms of NO release. At the end of the perfusion, microsomes were prepared and used for kinetic analysis. Except for 2D1, NO reduced the Vmax of all the model reactions studied, although to a varying degree. However, the effects of NO donors on Km were more diverse. Whereas the Km values for testosterone 6β-hydroxylation (3A2) and 16α-hydroxylation (2C11) significantly decreased, the values for chlorzoxazone 6-hydroxylation (2E1), dextromethorphan N-demethylation (3A2), and high affinity ethoxyresorufin O-dealkylation (1A1/2) significantly increased in the presence of NO donors. Furthermore, the Km values for the high-affinity component of dextromethorphan O-demethylation and benzyloxyresorufin O-dealkylation remained unchanged. These results indicate that NO can potentially change both the Vmax and Km of various substrates selectively and confirm our previous findings that the activity of CYP2D1 is not affected by NO donors.

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

  • doi:10.1124/dmd.105.003848.

  • ABBREVIATIONS: P450, cytochrome P450; NO, nitric oxide; IPRL, isolated perfused rat liver; Vmax, maximum velocity of metabolism; Km, Michaelis-Menten constant; CLint, intrinsic clearance; SNP, sodium nitroprusside; ISDN, isosorbide dinitrate; CLZ, chlorzoxazone; 6-HCLZ, 6-hydroxychlorzoxazone; DM, dextromethorphan; MXM, methoxymorphinan; DT, dextrorphan; R, resorufin; BR, benzyloxyresorufin; ER, ethoxyresorufin; T, testosterone; 6β-HT, 6β-hydroxytestosterone; 16α-HT, 16α-hydroxytestosterone; NOx, nitrate/nitrite; v, rate of metabolism; [s], substrate concentration; n, Hill coefficient; CLtotal, total intrinsic clearance; CLmax, maximum clearance.

    • Received January 27, 2005.
    • Accepted March 16, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (6)
Drug Metabolism and Disposition
Vol. 33, Issue 6
1 Jun 2005
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Research ArticleArticle

ENZYME-SELECTIVE EFFECTS OF NITRIC OXIDE ON AFFINITY AND MAXIMUM VELOCITY OF VARIOUS RAT CYTOCHROMES P450

Ragini Vuppugalla and Reza Mehvar
Drug Metabolism and Disposition June 1, 2005, 33 (6) 829-836; DOI: https://doi.org/10.1124/dmd.105.003848

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Research ArticleArticle

ENZYME-SELECTIVE EFFECTS OF NITRIC OXIDE ON AFFINITY AND MAXIMUM VELOCITY OF VARIOUS RAT CYTOCHROMES P450

Ragini Vuppugalla and Reza Mehvar
Drug Metabolism and Disposition June 1, 2005, 33 (6) 829-836; DOI: https://doi.org/10.1124/dmd.105.003848
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