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Research ArticleArticle

Cytochrome P450 Isozymes Involved in Lisofylline Metabolism to Pentoxifylline in Human Liver Microsomes

Sun H. Lee and John T. Slattery
Drug Metabolism and Disposition December 1997, 25 (12) 1354-1358;
Sun H. Lee
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John T. Slattery
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Abstract

We describe the kinetics of pentoxifylline formation from lisofylline in human liver microsomes using selective inhibitors of cytochrome P450 isozymes, correlation studies with specific isozyme activities, and cDNA-expressed human CYP1A2 and 2E1. A biphasic model fitted the data best for the formation of pentoxifylline,Km1 = 0.282 ± 0.135 μM, Vmax1 = 0.003 ± 0.001 nmol/min/mg protein, Km2= 158 ± 42.6 μM andVmax2 =0.928 ± 0.308 nmol/min/mg (N = 4). Pentoxifylline formation by the lowKm isoform (200 μM lisofylline) required NADPH, was not inhibited by any isozyme-specific P450 inhibitor, and was inhibited only 10% and 20%, respectively, by aminobenzotriazole and N-octamylamine. We concluded that the low Km enzyme was not a cytochrome P450. At 5 μM of lisofylline the CYP1A2 inhibitor, furafylline, inhibited pentoxifylline formation by 58.8%, and the nonspecific CYP2E1 inhibitor, diethyldithiocarbamate, inhibited pentoxifylline formation by 21.7%. When preincubated with furafylline plus diethyldithiocarbamate, inhibition of pentoxifylline formation was increased 71.4%. Microsomal CYP1A2 activity correlated with pentoxifylline formation (r2 = 0.870,p < 0.001). However, CYP2E1 activity did not correlate with pentoxifylline formation (r2 = 0.143, p = 0.181). Baculovirus insect cell expressed human CYP1A2 formed pentoxifylline at 0.987 nmol/min/nmol cytochrome P450 at 5 μM lisofylline. cDNA expressed CYP2E1 did not catalyze formation of pentoxifylline. Diethyldithiocarbamate inhibited pentoxifylline formation by 85.7% in cDNA expressed CYP1A2. We conclude that CYP1A2 is the high affinity enzyme catalyzing pentoxifylline formation from lisofylline.

Footnotes

  • Send reprint requests to: John T. Slattery, Ph.D., Department of Pharmaceutics, Box 357610, University of Washington, Seattle, WA 98195-7610. E-mail : jts{at}u.washington.edu.

  • ↵1 Present address: Department of Pharmacokinetics, Biotech Research Institute, LG Chemical Ltd/Research Park, Taejon, South Korea.

  • Supported in part by grants CA18029 and GM32165 from the National Institutes of Health.

  • Abbreviations used are::
    NADPH
    β-nicotinamide adenine dinucleotide phosphate (reduced form)
    HPLC
    high-performance liquid chromatography
    DDC
    diethyldithiocarbamate
    ABT
    1-aminobenzotriazole
    • Received March 31, 1997.
    • Accepted July 28, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 12
1 Dec 1997
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Research ArticleArticle

Cytochrome P450 Isozymes Involved in Lisofylline Metabolism to Pentoxifylline in Human Liver Microsomes

Sun H. Lee and John T. Slattery
Drug Metabolism and Disposition December 1, 1997, 25 (12) 1354-1358;

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Research ArticleArticle

Cytochrome P450 Isozymes Involved in Lisofylline Metabolism to Pentoxifylline in Human Liver Microsomes

Sun H. Lee and John T. Slattery
Drug Metabolism and Disposition December 1, 1997, 25 (12) 1354-1358;
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