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Research ArticleArticle

Identification of Human Hepatic Cytochrome P450 Sources of N-alkylprotoporphyrin IX after Interaction with Porphyrinogenic Xenobiotics, Implications for Detection of Xenobiotic-Induced Porphyria in Humans

James A. Lavigne, Kanji Nakatsu and Gerald S. Marks
Drug Metabolism and Disposition July 2002, 30 (7) 788-794; DOI: https://doi.org/10.1124/dmd.30.7.788
James A. Lavigne
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Kanji Nakatsu
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Gerald S. Marks
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Abstract

Porphyrinogenicity of certain xenobiotics depends upon mechanism-based inactivation of specific cytochrome P450 (P450) enzymes, followed by formation of N-alkylprotoporphyrin IX (N-alkylPP). Examination of the porphyrinogenicity of xenobiotics in animals and extrapolation of the results to humans is associated with ambiguity due, in part, to differences between P450 enzymes. The goal of this study was to develop an in vitro test for the detection of N-alkylPPs, produced in human liver after administration of xenobiotics found to be porphyrinogenic in animals. This goal was achieved using fluorometry to detectN-alkylPP formation following mechanism-based inactivation by porphyrinogenic xenobiotics of single cDNA-expressed human P450 enzymes in microsomes prepared from baculovirus-infected insect cells (Supersomes) and in human liver microsomes. The following combinations of P450 enzymes were major sources of N-alkylPPs in Supersomes: CYP3A4 [3-[(arylthio)-ethyl]sydnone (TTMS)]; CYP1A2 and 2C9 [3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine (4-ethyl DDC)]; and CYP2C9, 2D6, and 3A4 [allylisopropylacetamide (AIA)]. Whereas similarities were found between results with human enzymes in Supersomes and their rat orthologs in rat liver microsomes, some differences were found. The results with TTMS and AIA, but not with 4-ethyl DDC, were the same in individual human enzymes expressed in Supersomes and human liver microsomes. We conclude that some differences exist between human liver P450 enzymes and their rat P450 orthologs in liver microsomes. It would therefore be prudent when dealing with xenobiotics in which porphyrinogenicity depends uponN-alkylPP formation to supplement animal data with studies using human P450 enzymes.

Footnotes

  • Supported by the Canadian Institutes of Health Research.

  • ↵2 The N-alkyl moiety is derived from AIA by addition of a hydroxyl group to the internal carbon of the allyl group and a porphyrin nitrogen to the terminal carbon of the allyl group. The N-alkyl moiety is converted in a secondary reaction into a lactone by reaction of the hydroxyl with an amide group (Ortiz de Montellano et al., 1984).

  • Abbreviations used are::
    TTMS
    3-[(arylthio)-ethyl]sydnone
    4-ethyl DDC
    3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine
    AIA
    allylisopropylacetamide
    P450
    cytochrome P450
    N-alkylPP
    N-alkylprotoporphyrin
    N-AIAPP
    N-AIA protoporphyrin
    N-vinylPP
    N-vinylprotoporphyrin
    N-ethylPP
    N-ethylprotoporphyrin
    TLC
    thin layer chromatography
    LLD
    lower limit of detection
    • Received September 18, 2001.
    • Accepted March 19, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (7)
Drug Metabolism and Disposition
Vol. 30, Issue 7
1 Jul 2002
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Research ArticleArticle

Identification of Human Hepatic Cytochrome P450 Sources of N-alkylprotoporphyrin IX after Interaction with Porphyrinogenic Xenobiotics, Implications for Detection of Xenobiotic-Induced Porphyria in Humans

James A. Lavigne, Kanji Nakatsu and Gerald S. Marks
Drug Metabolism and Disposition July 1, 2002, 30 (7) 788-794; DOI: https://doi.org/10.1124/dmd.30.7.788

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Research ArticleArticle

Identification of Human Hepatic Cytochrome P450 Sources of N-alkylprotoporphyrin IX after Interaction with Porphyrinogenic Xenobiotics, Implications for Detection of Xenobiotic-Induced Porphyria in Humans

James A. Lavigne, Kanji Nakatsu and Gerald S. Marks
Drug Metabolism and Disposition July 1, 2002, 30 (7) 788-794; DOI: https://doi.org/10.1124/dmd.30.7.788
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