Document Detail


Interactions between CYP2E1 and CYP2B4: effects on affinity for NADPH-cytochrome P450 reductase and substrate metabolism.
MedLine Citation:
PMID:  23043184     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Studies in microsomal and reconstituted systems have shown that the presence of one cytochrome P450 isoform can significantly influence the catalytic activity of another isoform. In this study, we assessed whether CYP2E1 could influence the catalytic activity of CYP2B4 under steady-state turnover conditions. The results show that CYP2E1 inhibits CYP2B4-mediated metabolism of benzphetamine (BNZ) with a K(i) of 0.04 µM. However, CYP2B4 is not an inhibitor of CYP2E1-mediated p-nitrophenol hydroxylation. When these inhibition studies were performed with the artificial oxidant tert-butyl hydroperoxide, CYP2E1 did not significantly inhibit CYP2B4 activity. Determinations of the apparent K(M) and k(cat) of CYP2B4 for CPR in the presence of increasing concentrations of CYP2E1 revealed a mixed inhibition of CYP2B4 by CYP2E1. At low concentrations of CYP2E1, the apparent K(M) of CYP2B4 for CPR increased up to 23-fold with virtually no change in the k(cat) for the reaction, however, at higher concentrations of CYP2E1, the apparent K(M) of CYP2B4 for CPR decreased to levels similar to those observed in the absence of CYP2E1 and the k(cat) also decreased by 11-fold. Additionally, CYP2E1 increased the apparent K(M) of CYP2B4 for BNZ by 8-fold and the apparent K(M) did not decrease to its original value when saturating concentrations of CPR were used. While the individual apparent K(M) values of CYP2B4 and CYP2E1 for CPR are similar, the apparent K(M) of CYP2E1 for CPR in the presence of CYP2B4 decreased significantly, thus suggesting that CYP2B4 enhances the affinity of CYP2E1 for CPR and this may allow CYP2E1 to out-compete CYP2B4 for CPR.
Authors:
Cesar Kenaan; Erin V Shea; Hsia-lien Lin; Haoming Zhang; Matthew J Pratt-Hyatt; Paul F Hollenberg
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-05
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  41     ISSN:  1521-009X     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2012-12-21     Completed Date:  2013-06-25     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  101-10     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Aryl Hydrocarbon Hydroxylases / metabolism*
Base Sequence
Catalysis
Cytochrome P-450 CYP2E1 / metabolism*
DNA Primers
Hydroxylation
NADPH-Ferrihemoprotein Reductase / metabolism*
Substrate Specificity
Grant Support
ID/Acronym/Agency:
CA16954/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/DNA Primers; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/Cytochrome P-450 CYP2E1; EC 1.14.14.1/cytochrome P-450 CYP2B4 (rabbit); EC 1.6.2.4/NADPH-Ferrihemoprotein Reductase
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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