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Research ArticleArticle

Formation of Guanoxabenz from Guanabenz in Human Liver

A new metabolic marker for CYP1A2

Bernd Clement and Mark Demesmaeker
Drug Metabolism and Disposition November 1997, 25 (11) 1266-1271;
Bernd Clement
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Mark Demesmaeker
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A new metabolic marker for CYP1A2

Abstract

The in vitro N-hydroxylation of guanabenz as well as the corresponding N-dehydroxylation of guanoxabenz has been previously detected in biotransformation studies with microsomal fractions of different species including human hepatic microsomes. Furthermore, the N-hydroxylation of guanabenz was found to be catalyzed by enriched cytochrome P450 (P450) fractions in reconstituted systems. Strong correlations between 7-ethoxyresorufinO-deethylation (r = 0.96;p < 0.001), caffeine N-demethylation (r = 0.92; p < 0.001), respectively, and guanabenz N-hydroxylation activities were demonstrated in 10 human liver microsomal preparations. Studies with microsomes from human B-lymphoblastoid cell lines expressing human cytochrome P450 enzymes proved that CYP1A2 is the major isozyme responsible for this metabolic pathway. Further, P450 isozymes did not show any detectable conversion rates. The reaction was inhibited in presence of the potent CYP1A2 inhibitors α-naphthoflavone (7,8-benzoflavone) and furafylline. The N-reduction of guanoxabenz to guanabenz exhibits a significant correlation to the benzamidoximeN-reduction after incubation with 10 human liver microsomal preparations (r = 0.97; p < 0.001). The formation of benzamidine from benzamidoxime was described previously to be catalyzed by the benzamidoxime reductase. These results suggest that the guanabenz N-hydroxylation is mediated via CYP1A2, whereas the corresponding guanoxabenzN-reduction is catalyzed by an enzyme system composed of cytochrome b5, NADH cytochromeb5-reductase, and benzamidoxime reductase. The high affinity of guanabenz to CYP1A2 and the distinct selectivity of this P450 isozyme toward guanabenz confirms the in vitro guanabenz N-hydroxylation to be a suitable metabolic marker for CYP1A2 in biotransformation studies.

Footnotes

  • Send reprint requests to: Professor Dr. Bernd Clement, Pharmazeutisches Institut, Christian-Albrechts-Universitat Kiel, Gutenbergstrasse 76, D-24118 Kiel, Germany.

  • Abbreviations used are::
    P450
    cytochrome P450
    TAO
    triacetylolendomycine
    HPLC
    high performance liquid chromatography
    • Received March 5, 1997.
    • Accepted July 25, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 11
1 Nov 1997
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Research ArticleArticle

Formation of Guanoxabenz from Guanabenz in Human Liver

Bernd Clement and Mark Demesmaeker
Drug Metabolism and Disposition November 1, 1997, 25 (11) 1266-1271;

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Research ArticleArticle

Formation of Guanoxabenz from Guanabenz in Human Liver

Bernd Clement and Mark Demesmaeker
Drug Metabolism and Disposition November 1, 1997, 25 (11) 1266-1271;
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