Document Detail


Novel CYP2B6 enzyme variants in a Rwandese population: functional characterization and assessment of in silico prediction tools.
MedLine Citation:
PMID:  23418033     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cytochrome P450 CYP2B6 is a highly polymorphic enzyme that metabolizes numerous drugs, pesticides, and environmental toxins. Sequence analysis of a Rwandese population identified eight functionally uncharacterized nonsynonymous variants c.329G>T (p.G110V), c.341T>C (p.I114T), c.444G>T (p.E148D), c.548T>G (p.V183G), c.637T>C (p.F213L), c.758G>A (p.R253H), c.835G>C (p.A279P), and c.1459C>A (p.R487S), and five novel alleles termed CYP2B6*33 to CYP2B6*37 were assigned. Recombinant expression in COS-1 cells and functional characterization using the antidepressant bupropion and the antiretroviral efavirenz (EFV) as substrates demonstrated complete or almost complete loss-of-function for variants p.G110V, p.I114T, p.V183G, and p.F213L, whereas p.E148D, p.R253H, p.A279P, and p.R487S variants were functional. The data were used to assess the predictive power of eight online available functional prediction programs for amino-acid changes. Although none of the programs correctly predicted the functionality of all variants, substrate docking simulation analyses indicated similar conformational changes by all four deleterious mutations within the enzyme's active site, thus explaining lack of enzymatic function for both substrates. Because low-activity alleles of CYP2B6 are associated with impaired EFV metabolism and adverse drug response, these results are of potential utility for personalized treatment strategies in HIV/AIDS therapy.
Authors:
Robert Radloff; Alain Gras; Ulrich M Zanger; Cécile Masquelier; Karthik Arumugam; Jean-Claude Karasi; Vic Arendt; Carole Seguin-Devaux; Kathrin Klein
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-03-11
Journal Detail:
Title:  Human mutation     Volume:  34     ISSN:  1098-1004     ISO Abbreviation:  Hum. Mutat.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-12     Completed Date:  2013-09-30     Revised Date:  2014-01-07    
Medline Journal Info:
Nlm Unique ID:  9215429     Medline TA:  Hum Mutat     Country:  United States    
Other Details:
Languages:  eng     Pagination:  725-34     Citation Subset:  IM    
Copyright Information:
© 2013 Wiley Periodicals, Inc.
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MeSH Terms
Descriptor/Qualifier:
Aryl Hydrocarbon Hydroxylases / chemistry,  genetics*
Blotting, Western
Genetics, Population*
Haplotypes
Humans
Molecular Dynamics Simulation
Mutation
Oxidoreductases, N-Demethylating / chemistry,  genetics*
Polymorphism, Single Nucleotide
Rwanda
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

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


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