ORIGINAL ARTICLESIdentification of a novel specific CYP2B6 allele in Africans causing impaired metabolism of the HIV drug efavirenzWang, Juea; Sönnerborg, Andersb; Rane, Andersc; Josephson, Filipc; Lundgren, Stefanc; Ståhle, Larsd; Ingelman-Sundberg, MagnusaAuthor Information aDivision of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institute, Stockholm bDivision of Infectious Diseases, Department of Medicine, Karolinska Institute at Karolinska University Hospital, Huddinge cDivision of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital, Huddinge dAstraZeneca R&D, Södertälje, Sweden Correspondence and requests for reprints to Magnus Ingelman-Sundberg, Division of Molecular Toxicology, IMM, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden Tel: +46 8 524 87735; fax: +46 8 337327; e-mail: [email protected] Received 4 July 2005 Accepted 16 October 2005 Pharmacogenetics and Genomics: March 2006 - Volume 16 - Issue 3 - p 191-198 doi: 10.1097/01.fpc.0000189797.03845.90 Buy Metrics Abstract The non-nucleoside reverse transcriptase inhibitor efavirenz is mainly metabolised by the polymorphic cytochrome P450 enzyme CYP2B6. Genomic DNA from four subjects in a group of 51 patients being treated with efavirenz and having surprisingly high plasma concentrations were screened by direct sequencing for mutations in the CYP2B6 gene. Four exonic single nucleotide polymorphisms (SNPs), 516G>T, 714G>A, 785A>G and 983T>C, and eight intronic SNPs were identified. Haplotype analysis revealed that 983T>C was linked with 785A>G defining a novel allele, CYP2B6*16. This allele was present in totally five of the patients. The CYP2B6.16 cDNA was expressed in yeast and HEK293 cells and significantly less protein was formed compared to the wild-type cDNA, in both heterologous systems. By contrast, the catalytic activity of the enzyme variant was not different from the CYP2B6.1 enzyme, using bupropion as a probe substrate. The CYP2B6*16 allele was not found in Swedes, was present at 4% frequency among Turks, but was common among Africans. The steady-state level of efavirenz was significantly higher in the five carriers of CYP2B6*16, being of African origin, compared to the other patients. Higher efavirenz concentrations were also seen in carriers of 516G>T (CYP2B6*6 and CYP2B6*9). In conclusion, a novel CYP2B6*16 allele causing less expression of the corresponding enzyme was identified and found to influence the metabolism of efavirenz in vivo, a finding that is of potential impact for anti-HIV therapy in black populations. © 2006 Lippincott Williams & Wilkins, Inc.