A specific mutation of a gene which influences the expression of a glycoprotein transporter protein involved in the body’s resistance to drugs and other toxins is detailed in a research letter in this week’s issue of THE LANCET. Results of the study suggest that drug therapies used in treating HIV-1 infection (notably protease inhibitors ) may not be as effective in West African and African American ethnic groups compared with Caucasian populations.
The variability of P-glycoprotein expression between individuals is linked to a C3435T alteration of the human MDR1 gene. Concentration of P-glycoprotein in intestinal epithelial cells and in some lymphoid cells is substantially lower in people with the T/T genotype than those with the C/C genotype. Matthias Schwab and colleagues from Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, compared allele frequencies of the C3435T polymorphism in random samples of west African, African American, Caucasian, and Japanese people. The investigators recorded a substantially higher frequency of the high-expression C/C genotype in West Africans and African Americans (142 of 172 [83%] and 25 of 41 [61%], respectively), than in caucasian people (139 of 537 [26%]).
Matthias Schwab comments: "The C/C genotype could be a factor restricting access of HIV-1 protease inhibitors to their major cellular target, the CD4+ T-lymphocytes and to other sanctuary sites of the virus such as brain and testis, which are known to express P-glycoprotein. Further studies are needed to clarify the mechanism by which the C3435T polymorphism leads to decreased P-glycoprotein expression and to define its role as a susceptibility factor for infectious diseases and drug treatment with P-glycoprotein substrates. These findings could affect use of drugs that are P-glycoprotein substrates (such as HIV-1 protease inhibitors and ciclosporin) in African populations."
Contact: Dr Matthias Schwab, Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376 Stuttgart, Germany; T)49-711-8101-3728 F) 49-711-85-92-95 E) matthias.schwab@ikp-stuttgart.de
Journal
The Lancet