Molecular determinants of the response to malaria therapeutics

Abstract

Tese dout., Bioquímica, Universidade do Algarve, 2007The overall aim of this thesis was the analysis of the genetic variability in genes coding for proteins important in drug metabolism. The analysis of the metabolism of antimalarial drugs, particularly amodiaquine, and the possible contribution of biotransformation for the susceptibility to the disease was also studied. The results obtained in the genotyping studies in the populations of Guinea- Bissau, Portugal, Sao Tome and Principe, Thailand and Zanzibar showed a high interethnic variability. A high variability in Africans was observed. The study of the effect of CYP2C8 genotype in the AQ treatment outcome revealed that none of the alleles analysed influence therapeutic efficacy. In the analysis of amodiaquine metabolism we focused particularly on the metabolite desethylamodiaquine. Using microsomes enriched with recombinant CYPs, a reduction in drug concentration was observed in the presence of CYP1A1. The posterior investigation of the genetic variation in CYP1A1 identified several SNPs, particularly in the Papua New Guinea population. However, this variability could not be associated with the extreme variability observed in pharmacokinetic parameters. The study on the influence of the GSTT1 null genotype in uncomplicated malaria revealed that the lack of this gene seems to be a protective factor in this diseaseFundação para a Ciência e Tecnologia (FCT