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Research ArticleArticle

Cytochrome CYP Sources of N-Alkylprotoporphyrin IX after Administration of Porphyrinogenic Xenobiotics to Rats

Simon G. W. Wong, Eva H. Lin and Gerald S. Marks
Drug Metabolism and Disposition September 1999, 27 (9) 960-965;
Simon G. W. Wong
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Eva H. Lin
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Gerald S. Marks
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Abstract

Cytochrome P-450 (CYP) 3A2 and CYP2C11 are sources of 70 and 30%, respectively, of N-vinylprotoporphyrin IX (N-vinylPP) formation after administration of 3-[(arylthio)ethyl]sydnone (TTMS) to rats. Female rats receiving TTMS were pretreated with dexamethasone, which induces CYP3A1 preferentially to CYP3A2. The resulting 12-fold increase in N-vinylPP formation showed that CYP3A1 was also a source ofN-vinylPP. Phenobarbital (PB) pretreatment, which induces CYP2B1/2 and 3A1/2 in male rats, increasedN-vinylPP formation after TTMS administration. Troleandomycin, a selective CYP3A inhibitor, was unable to decrease TTMS-mediated N-vinylPP formation in PB-treated male rats, indicating that CYP2B1/2 were sources ofN-vinylPP. This conclusion was supported by demonstrating a 15-fold increase in TTMSinducedN-vinylPP formation in female rats after CYP2B1/2 induction with PB pretreatment. Allylispropylacetamide (AIA) inactivates rat CYP2B1/2, 2C6, 2C7, 2C11, and 3A1/2. Troleandomycin was unable to decrease N-AIA protoporphyrin IX adduct (N-AIAPP) formation, showing that CYP3A1/2 were not susceptible to AIA-mediated N-alkylation.N-AIAPP formation in females was approximately 30% of that in males, and thus we attribute 30% of N-AIAPP formation in males to the non-gender-specific isozymes (CYP2C6, 2C7, and/or 2B1/2), whereas approximately 70% originates from CYP2C11. PB treatment in female rats resulted in a 5-fold increase inN-AIAPP formation, showing that CYP2B1/2 were also susceptible to N-alkylation mediated by AIA. 1-Aminobenzotriazole elicited formation of equivalent amounts ofN′N-aryl bridged protoporphyrin IX in male and female rat liver, demonstrating that nonselective mechanism-based inactivation is accompanied by nonselective conversion of the CYP heme moieties to N′N-aryl bridged protoporphyrin IX.

Footnotes

  • Send reprint requests to: Gerald S. Marks, Ph.D., Department of Pharmacology and Toxicology, Faculty of Health Sciences, Queen’s University, Kingston, Ontario, Canada K7L 3N6. E-mail:gsm{at}post.queensu.ca

  • This research was supported by the Medical Research Council of Canada.

  • Abbreviations used are::
    N-alkylPP
    N-alkylprotoporphyrin IX
    N-vinylPP
    N-vinylprotoporphyrin IX
    N-ethylPP
    N-ethylprotoporphyrin IX
    4-ethylDDC
    3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine
    TTMS
    3-[(arylthio)ethyl]sydnone
    CYP
    cytochrome P-450
    PB
    phenobarbital
    DEX
    dexamethasone
    TAO
    troleandomycin
    ABT
    1-aminobenzotriazole
    AIA
    allylisopropylacetamide
    N-AIAPP
    N-allyisopropylacetamide protoporphyrin IX (adduct)
    NNAPP
    N′N-aryl bridged protoporphyrin IX
    ERND
    erythromycin N-demethylase
    • Received December 21, 1998.
    • Accepted April 30, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (9)
Drug Metabolism and Disposition
Vol. 27, Issue 9
1 Sep 1999
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Research ArticleArticle

Cytochrome CYP Sources of N-Alkylprotoporphyrin IX after Administration of Porphyrinogenic Xenobiotics to Rats

Simon G. W. Wong, Eva H. Lin and Gerald S. Marks
Drug Metabolism and Disposition September 1, 1999, 27 (9) 960-965;

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Research ArticleArticle

Cytochrome CYP Sources of N-Alkylprotoporphyrin IX after Administration of Porphyrinogenic Xenobiotics to Rats

Simon G. W. Wong, Eva H. Lin and Gerald S. Marks
Drug Metabolism and Disposition September 1, 1999, 27 (9) 960-965;
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