P-glycoprotein, a therapeutic target in cancer, new studies about their genetic polymorphisms and their modulation by natural products performed in Cuba

Abstract

P-glycoprotein (P-gp) is a transmembrane active efflux pump for a variety of drugs and the most extensively studied ATP-binding cassette (ABC) coded by MDR1 gene. The importance of P-gp in drug-drug interactions is being identified. ABCB1 polymorphisms also contribute to variability in P-gp function. Single-nucleotide polymorphisms (SNPs) in MDR1 gene are associated with phenotypic variation in P-gp expression levels of tissue. The wobble C3435T polymorphism at exon 26 has been associated with different expression levels and activity. Differences in allele frequency of the C3435T polymorphism have been demonstrated between ethnic groups. Frequencies of the variant C3435T were evaluated in 140 Cuban unrelated healthy volunteers (73 males and 67 females). Results showed: 65 subjects (46,4%) expressed CC, 58 (41,4%) expressed CT variant and 17 (12,1%) presented the TT variant. Results fit to Cuban population origins. On the other hands, inhibition or induction of P-gp by co-administered drugs and herbal constituents may result in pharmacokinetic interactions leading to unexpected toxicities or under treatment. Results about modulation of different natural Cuban products, like Mangifera indica L extract, mangiferin and Thalassia testidinum extract, on function of P-gp are presented. All the products were able to reduce P-gp activity (assessed by rhodamine-123 accumulation) in treated hepatocytes and tumor cell lines (HepG2, 4T1, Caco2). In particular mangiferin, the main component of Mangifera indica L extract, was less active than the extract. Our results suggest these products should be examined for potential pharmacokinetic drug interactions in vivo. The study of interactions and of genetic factors affecting pharmacokinetics and pharmacodynamics is expected to improve drug safety and will enable individualized drug therapy.