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Research ArticleArticle

Mechanism-Based Inactivation of Cytochromes P450 2B1 and P450 2B6 by 2-Phenyl-2-(1-piperidinyl)propane

Jarin Chun, Ute M. Kent, Rachel M. Moss, Lawrence M. Sayre and Paul F. Hollenberg
Drug Metabolism and Disposition August 2000, 28 (8) 905-911;
Jarin Chun
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Ute M. Kent
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Rachel M. Moss
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Lawrence M. Sayre
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Paul F. Hollenberg
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Abstract

2-Phenyl-2-(1-piperidinyl)propane (PPP), an analog of phencyclidine, was tested for its ability to inactivate cytochrome P450s (P450s) 2B1 and 2B6. PPP inactivated the 7-(benzyloxy)resorufinO-dealkylation activity of liver microsomes obtained from phenobarbital-induced rats with a KI of 11 μM. The 7-ethoxy-4-(trifluoromethyl)coumarinO-deethylation activity of purified rat liver P450 2B1 and expressed human P450 2B6 was inactivated by PPP in a reconstituted system containing NADPH-cytochrome P450 reductase and lipid. In the presence of NADPH, the loss of activity was time- and concentration-dependent, and followed pseudo first order kinetics. The rate of inactivation for P450 2B1 was 0.3 min−1, and the concentration of PPP required to achieve half-maximal inactivation was 12 μM. The time for 50% of the P450 2B1 to become inactivated at saturating concentrations of PPP was 2.5 min. P450 2B6 was inactivated with a kinact of 0.07 min−1, aKI of 1.2 μM, and at1/2 of 9.5 min. The inactivated P450s 2B1 and 2B6 lost about 25 and 15%, respectively, of their ability to form a CO-reduced complex, suggesting that the loss of activity was caused by a PPP modification of the apoprotein rather than the heme. The estimated partition ratio for P450s 2B1 and 2B6 with PPP was 31 and 15, respectively. The inactivation was not reversible and reductase activity was not affected. Coincubation of P450 2B1 and 2B6 with PPP and NADPH in the presence of an alternate substrate protected both enzymes from inactivation. The exogenous nucleophile GSH did not affect the rate of inactivation. PPP-inactivated P450s 2B1 and 2B6 were recognized on Western blots by an antibody generated to phencyclidine that had been conjugated to BSA. Stoichiometries of 1.4:1 and 0.7:1 were determined for the binding of a [3H]PPP metabolite to P450 2B1 and 2B6, respectively.

Footnotes

  • Send reprint requests to: Dr. Paul F. Hollenberg, Department of Pharmacology, Medical Science Research Building III, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0632. E-mail: phollen{at}umich.edu

  • ↵1 Part of this work was presented at the 1999 meeting of the International Society for the Study of Xenobiotics in Nashville, TN.

  • ↵2 J.C. was a recipient of the 1998 University of Michigan Medical School Summer Biomedical Research Fellowship Award and the 1999 summer ASPET Research Fellowship Award.

  • ↵3 R.M.M. was from Tulane University and was a recipient of a summer ASPET Undergraduate Research Fellowship Award.

  • These studies were supported in part by National Institutes of Health Grants CA 16954 (P.F.H.) from the National Cancer Institute, and GM48812 (L.M.S.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

  • Abbreviations used are::
    P450
    cytochrome P450 (nomenclature from Nelson et al., 1996)
    reductase
    NADPH-cytochrome P450 reductase
    DLPC
    dilauroyl-l-α-phosphatidylcholine
    7-EFC
    7-ethoxy-4-(trifluoromethyl)coumarin
    PPP
    2-phenyl2-(1-piperidinyl)propane
    PCP
    phencyclidine
    PCHAP
    5-[N-(1′-phenylcyclohexyl)amino]pentanoic acid
    • Received December 21, 1999.
    • Accepted April 29, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (8)
Drug Metabolism and Disposition
Vol. 28, Issue 8
1 Aug 2000
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Research ArticleArticle

Mechanism-Based Inactivation of Cytochromes P450 2B1 and P450 2B6 by 2-Phenyl-2-(1-piperidinyl)propane

Jarin Chun, Ute M. Kent, Rachel M. Moss, Lawrence M. Sayre and Paul F. Hollenberg
Drug Metabolism and Disposition August 1, 2000, 28 (8) 905-911;

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Research ArticleArticle

Mechanism-Based Inactivation of Cytochromes P450 2B1 and P450 2B6 by 2-Phenyl-2-(1-piperidinyl)propane

Jarin Chun, Ute M. Kent, Rachel M. Moss, Lawrence M. Sayre and Paul F. Hollenberg
Drug Metabolism and Disposition August 1, 2000, 28 (8) 905-911;
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