The present study investigated CYP2B6 genetic variability by sequencing genomic DNA samples of African-American, Ghanaian, Taiwanese, Japanese and Korean subjects throughout all exons and exon-intron boundaries. The most common nonsynonymous single nucleotide polymorphisms (SNPs) were 15631G>T (Q172H) and 18053A>G (K262R, together defining allele 2B6*6), both of which had frequencies close to 50% in Ghanaians and 30% in African-Americans. These SNPs have recently been shown to affect efavirenz pharmacokinetics and response in HIV patients. Eight new missense mutations (76A>T [T26S], 83A>G [D28G], 85C>A, 86G>C [both R29T], 15618C>T [T168I],18038G>A [D257N], 21034C>T [R336C], 21498C>A [[P428T]), three new silent mutations and two new intronic SNPs defining six novel alleles (*17A and B, *18, *19, *20, *21) were identified. Heterologous expression in COS-1 cells revealed pronounced reduction in expression and/or bupropion hydroxylase activity for variants T1681, D257N, R336C and P428T, whereas the triple mutant 2B6.17 (THS, D28G, R29T) appeared to be functionally normal. These data extend the CYP2B6 knowledge base and should be particularly relevant for anti-HIV-therapy with efavirenz.
