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Research ArticleArticle

Selective Involvement of Cytochrome P450 2D Subfamily in In Vivo 4-Hydroxylation of Amphetamine in Rat

Michael Y. L. Law, Matthew H. Slawson and David E. Moody
Drug Metabolism and Disposition March 2000, 28 (3) 348-353;
Michael Y. L. Law
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Matthew H. Slawson
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David E. Moody
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Abstract

The cytochrome P450 (P450) 2D subfamily catalyzes ring hydroxylation of amphetamines. We tested the hypothesis that P450 2D is selectively involved in amphetamine 4-hydroxylation. Urinary elimination of 4-hydroxyamphetamine and amphetamine was determined in male Sprague-Dawley rats pretreated with P450 inducers and inhibitors. The urinary 24-h metabolic ratio (amphetamine/4-hydroxyamphetamine) was not affected by the inducers 3-methylcholanthrene, isosafrole, phenobarbital, ethanol, pregnenolone-α-carbonitrile, and clofibrate. Isosafrole did, however, increase amphetamine elimination along with urine volume. Urinary elimination of 4-hydroxyamphetamine was significantly decreased by, and the metabolic ratio increased by, the inhibitors 1-aminobenzotriazole, CCl4, quinidine, quinine, and primaquine. Diallyl sulfide and troleandomycin had no effect. In rat liver microsomes primaquine was shown to be an inhibitor of 2D activity. Urine 4-hydroxyamphetamine content correlated strongly (r2 = 0.989) with microsomal P450 2D activity in parallel-treated rats. These studies also substantiate that 4-hydroxylation of amphetamine is selectively performed by the P450 2D subfamily in the rat.

Footnotes

  • Send reprint requests to: David E. Moody, Ph.D., University of Utah, Center for Human Toxicology, 20 S 2030 E, Rm. 490, Salt Lake City, Utah 84112-9457. E-mail:dmoody{at}alanine.pharm.utah.edu

  • ↵1 Current address: Chattem, Inc., 1715 West 38th Street, Chattanooga, TN 37409.

  • This work was supported in part by United States Public Health Service Grants DA05102 and DA10100.

  • ↵3 The metabolic activity of P450 2D in human liver is the result of expression of a single gene product, P450 2D6; however, activity in the rat results from expression of four genes,2D1, 2D2, 2D3, and2D5 (Matsunaga et al., 1989). As most of the work reported or cited in this paper does not distinguish a specific rat gene product, the subfamily term P450 2D will be used when discussing the rat enzymes.

  • Abbreviations used are::
    P450
    cytochrome P450
    SD
    Sprague-Dawley
    MDMA
    methylenedioxymethamphetamine
    PCN
    pregnenolone-α-carbonitrile
    EROD
    ethoxyresorufinO-deethylation
    PROD
    pentoxyresorufinO-dealkylation
    • Received April 23, 1999.
    • Accepted December 8, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (3)
Drug Metabolism and Disposition
Vol. 28, Issue 3
1 Mar 2000
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Research ArticleArticle

Selective Involvement of Cytochrome P450 2D Subfamily in In Vivo 4-Hydroxylation of Amphetamine in Rat

Michael Y. L. Law, Matthew H. Slawson and David E. Moody
Drug Metabolism and Disposition March 1, 2000, 28 (3) 348-353;

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Research ArticleArticle

Selective Involvement of Cytochrome P450 2D Subfamily in In Vivo 4-Hydroxylation of Amphetamine in Rat

Michael Y. L. Law, Matthew H. Slawson and David E. Moody
Drug Metabolism and Disposition March 1, 2000, 28 (3) 348-353;
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