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Research ArticleArticle

Evidence Supporting the Interaction of CYP2B4 and CYP1A2 in Microsomal Preparations

George F. Cawley, Shuxin Zhang, Russell W. Kelley and Wayne L. Backes
Drug Metabolism and Disposition December 2001, 29 (12) 1529-1534;
George F. Cawley
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Shuxin Zhang
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Russell W. Kelley
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Wayne L. Backes
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Abstract

Recent studies have demonstrated that the catalytic behavior of one cytochrome P450 (P450) enzyme can be influenced by the presence of a second P450. This effect has been observed using reconstituted systems containing reductase, CYP2B4, and CYP1A2, primarily at subsaturating reductase. Addition of 1A2 caused a 75% inhibition of CYP2B4-dependent 7-pentoxyresorufin-O-dealkylation (PROD). Conversely, CYP2B4-dependent benzphetamine (bzp) demethylation did not exhibit this response after CYP1A2 addition. Addition of CYP2B4 to a reconstituted system containing reductase and CYP1A2 caused synergism of CYP1A2-dependent 7-ethoxyresorufin-O-dealkylation (EROD). This behavior was consistent with the formation of heteromeric CYP1A2-CYP2B4 complexes with altered catalytic properties. Although such responses have been documented in reconstituted systems, they have not been demonstrated in microsomal preparations. The goal of the present study was to determine whether such interactions were observed in rabbit liver microsomes. In an effort to detect such changes, we took advantage of the differential effect of CYP1A2 on CYP2B4-selective PROD and bzp metabolism. Rabbits were treated with phenobarbital (PB), β-naphthoflavone (βNF), and both PB + βNF—conditions that enrich microsomes with CYP2B4, CYP1A2, or both enzymes, respectively. Benzphetamine demethylation activity was equivalently elevated in both the PB and the PB + βNF groups, consistent with the induction of CYP2B4 in both groups. In contrast, PROD activity in the PB + βNF group was less than 25% of that found in the PB-treated rabbits. These results demonstrate that the interactions observed in reconstituted systems are not an artifact of reconstitution but are observed under the more natural conditions of the microsomal membrane.

Footnotes

  • This work was supported by Grant ES04344 from the National Institute of Environmental Health Sciences.

  • Abbreviations used are::
    P450
    cytochrome P450
    PROD
    7-pentoxyresorufin-O-dealkylation
    EROD
    7-ethoxyresorufin-O-dealkylation
    PB
    phenobarbital
    βNF
    β-naphthoflavone
    7-PR
    7-pentoxyresorufin
    DLPC
    dilauroylphosphatidylcholine
    bzp
    benzphetamine
    OR
    NADPH-cytochrome P450 reductase
    • Received April 13, 2001.
    • Accepted August 28, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (12)
Drug Metabolism and Disposition
Vol. 29, Issue 12
1 Dec 2001
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Research ArticleArticle

Evidence Supporting the Interaction of CYP2B4 and CYP1A2 in Microsomal Preparations

George F. Cawley, Shuxin Zhang, Russell W. Kelley and Wayne L. Backes
Drug Metabolism and Disposition December 1, 2001, 29 (12) 1529-1534;

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Research ArticleArticle

Evidence Supporting the Interaction of CYP2B4 and CYP1A2 in Microsomal Preparations

George F. Cawley, Shuxin Zhang, Russell W. Kelley and Wayne L. Backes
Drug Metabolism and Disposition December 1, 2001, 29 (12) 1529-1534;
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