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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Novel CYP2B6 Enzyme Variants in a Rwandese Population: Functional Characterization and Assessment of In Silico Prediction Tools
Human Mutation, Volume 34, No. 5, Year 2013
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Description
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. © 2013 Wiley Periodicals, Inc.
Authors & Co-Authors
Radloff, Robert
Germany, Tubingen
Eberhard Karls Universität Tübingen
Gras, Alain
Luxembourg, Strassen
Luxembourg Institute of Health
Zanger, Ulrich M.
Germany, Tubingen
Eberhard Karls Universität Tübingen
Masquelier, Cécile
Luxembourg, Strassen
Luxembourg Institute of Health
Arumugam, Karthik
Luxembourg, Strassen
Luxembourg Institute of Health
Karasi, Jean Claude
Rwanda
Rwandese Biomedical Center at Kigali
Arendt, Vic
Luxembourg, Luxembourg
Centre Hospitalier de Luxembourg
Seguin-Devaux, Carole
Luxembourg, Strassen
Luxembourg Institute of Health
Klein, Kathrin
Germany, Tubingen
Eberhard Karls Universität Tübingen
Statistics
Citations: 36
Authors: 9
Affiliations: 4
Identifiers
Doi:
10.1002/humu.22295
ISSN:
10597794
e-ISSN:
10981004
Research Areas
Infectious Diseases
Study Design
Cross Sectional Study