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Novel CYP 2 B 6 Enzyme Variants in a Rwandese Population: Functional Characterization and Assessment of In Silico Prediction Tools
Author(s) -
Radloff Robert,
Gras Alain,
Zanger Ulrich M.,
Masquelier Cécile,
Arumugam Karthik,
Karasi JeanClaude,
Arendt Vic,
SeguinDevaux Carole,
Klein Kathrin
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22295
Subject(s) - cyp2b6 , biology , efavirenz , nonsynonymous substitution , in silico , population , enzyme , genetics , computational biology , biochemistry , cytochrome p450 , cyp3a4 , gene , antiretroviral therapy , genome , medicine , virus , environmental health , viral load
Cytochrome P 450 CYP 2 B 6 is a highly polymorphic enzyme that metabolizes numerous drugs, pesticides, and environmental toxins. Sequence analysis of a R wandese 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.