Document Detail


Bioactivation of chlorpyrifos by CYP2B6 variants.
MedLine Citation:
PMID:  22775490     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Chlorpyrifos (CPF), an organophosphorus (OP) pesticide, is bioactivated by cytochrome P450s (CYPs) to the active metabolite chlorpyrifos oxon (CPF-O). Given that human CYP2B6 has the highest intrinsic clearance (CL(int)) for CPF bioactivation, CYP2B6 polymorphisms may impact human susceptibility to CPF at real world environmental and occupational CPF exposure levels. CYP2B6.4,.5,.7, and .18 were over-expressed in mammalian COS-1 cells to assess the impact of CYP2B6 variants on the K(m) and V(max) for bioactivation of CPF. Cell lysates were incubated with CPF (0-100 μM) and the production of CPF-O was measured via HPLC analysis. CYP2B6 content was determined by western blot. CYP2B6.18 had neither detectable protein nor activity levels. The V(max) value for each remaining variant was significantly higher than wild-type (CYP2B6.1, V(max) 4.13 × 10(4) pmol/min/nmol CYP2B6), with CYP2B6.4,.5, and .7 having V(max) values of 4.52 × 10(5), 1.82 × 10(5), and 9.60 × 10(4) pmol/min/nmol CYP2B6, respectively. The K(m) values for these variants ranged from 0.39 to 1.09 μM and were not significantly different from wild-type. All active variants examined had significantly higher CL(int) than CYP2B6.1. Variants of CYP2B6 have altered capacity to bioactivate CPF and may affect individual susceptibility by altering the V(max) for CPF-O formation.
Authors:
Alice L Crane; Kathrin Klein; James R Olson
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-07-10
Journal Detail:
Title:  Xenobiotica; the fate of foreign compounds in biological systems     Volume:  42     ISSN:  1366-5928     ISO Abbreviation:  Xenobiotica     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-07     Completed Date:  2013-08-02     Revised Date:  2014-01-07    
Medline Journal Info:
Nlm Unique ID:  1306665     Medline TA:  Xenobiotica     Country:  England    
Other Details:
Languages:  eng     Pagination:  1255-62     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
African Americans / genetics
Animals
Aryl Hydrocarbon Hydroxylases / genetics*,  metabolism*
Biotransformation
Blotting, Western
COS Cells
Cercopithecus aethiops
Chlorpyrifos / chemistry,  metabolism*
European Continental Ancestry Group / genetics
Humans
Kinetics
Metabolic Networks and Pathways
Microsomes, Liver / enzymology
Oxidoreductases, N-Demethylating / genetics*,  metabolism*
Polymorphism, Genetic*
Substrate Specificity
Grant Support
ID/Acronym/Agency:
F30 ES020655/ES/NIEHS NIH HHS; F30 ES020655/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
EC 1.14.13.-/cytochrome P-450 CYP2B6; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.5.-/Oxidoreductases, N-Demethylating; JCS58I644W/Chlorpyrifos
Comments/Corrections

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


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