Document Detail


Stereospecific activation of the procarcinogen benzo[a]pyrene: a probe for the active sites of the cytochrome P450 superfamily.
MedLine Citation:
PMID:  7766605     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
It has been established previously that the sterochemistry of epoxidation of the procarcinogen benzo[a]pyrene determines the potency of the ultimate carcinogen. Herein we report that seven human P450s, five rodent P450s, and two bacterial P450s all convert B[a]P to the most potent carcinogenic often differ in both regioselectivity and stereoselectivity. This is likely due to the large size of the substrate molecule and its constraints in the active sites. Smaller substrates that can rotate more freely in the active site may be expected to have greater variations in binding orientations and therefore greater differences in stereoselectivities. Molecular mechanics is used to determine the specific amino acids responsible for the stereochemical outcome. Molecular dynamics is then used to strengthen the hypothesis that a single helical region, one that is likely to be conserved in all P450s, plays a primary role in determining the stereoselectivity of the reaction.
Authors:
J P Jones; M Shou; K R Korzekwa
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Biochemistry     Volume:  34     ISSN:  0006-2960     ISO Abbreviation:  Biochemistry     Publication Date:  1995 May 
Date Detail:
Created Date:  1995-07-03     Completed Date:  1995-07-03     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  6956-61     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, University of Rochester, New York 14642, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Benzo(a)pyrene / chemistry,  pharmacokinetics*
Binding Sites
Biotransformation
Cell Line
Cytochrome P-450 Enzyme System / metabolism*
Humans
Molecular Probes
Rabbits
Rats
Stereoisomerism
Grant Support
ID/Acronym/Agency:
ES06062/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Molecular Probes; 50-32-8/Benzo(a)pyrene; 9035-51-2/Cytochrome P-450 Enzyme System

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


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