Estudio de la influencia de polimorfismos en genes que codifican a las proteínas transportadoras hepáticasabcb1, abcb4, abcb11 y abcc2 en el riesgo de desarrollar hepatotoxicidad idiosincrásica y su expresión clínica

Abstract

Background: The canalicular transporters are involved in controlling the exposure to endogenous and exogenous compounds in the hepatocyte. Hence, an alteration in the function of these transporters could lead to hepatic damage. Thus, genetic variations in genes corresponding to this transport system could potentially be related to DILI development. Aims: To analyze if DILI patients have a higher prevalence of genotypic variants in the genes ABCB1, ABCB4, ABCB11 and ABCC2, which encode for the hepatic transporters P-gp, MDR3, BSEP and MRP2, respectively. To evaluate whether chemical structures with BSEP inhibiting properties in the causative agent combined with genetic polymorphisms enhance DILI susceptibility. Material and methods: This study was performed in 188 Spanish DILI patients and 219 healthy individuals as controls. Genotyping of the ABCB1 1236T>C and 3435T>C, ABCB4 3826A>G, ABCB11 1331T>C and ABCC2 -1549A>G, -24C>T, 1249G>A, 3972C>T and 4581G>A polymorphisms was performed using TaqMan probes. The ABCB1 2677G>T,A and ABCC2 -1774G>del polymorhisms were genotyped by direct sequencing. Results: The ABCB11 1331CC genotype was significantly more frequent in cases with hepatocellular damage compared to the control group, particularly in DILI patients exposed to non-steroidal antiinflammatory (NSAID) drugs. Furthermore, the 1331CC carriers had a higher prevalence of hepatocellular DILI development when exposed to carbocyclic systems present in the drug molecule. The frequency of the 1331CC genotype was higher in DILI patients exposed to drugs with <50% BSEP inhibitory capacity. The ABCC2 -1774deldel genotype was only seen in the DILI patients, while being absent in the controls. No significant differences in genotype or allele distributions were seen in the ABCC2 -1549A>G, -24C>T, 1249G>A, 3972C>T and 4581G>A, ABCB1 2677G>T,A, 1236T>C and 3435T>C and ABCB4 3826A>G polymorphisms compared to the controls. Conclusions: The ABCB11 1331 polymorphism in conjunction with specific chemical structures, such as a carbocyclic system, in the causative drug influence the risk of DILI. Hence, the BSEP transporter could be a new target for studies on pharmacological interactions of NSAIDs, due to the presence of carbocyclic systems as the only BESP inhibiting structure in many NSAIDs. This study do not support evidence for the ABCC2 polymorphisms -1549A>G, -24C>T, 1249G>A 3972C>T and 4581G>A as potential risk factors for DILI. However, the -1774G>del polymorphism could potentially contribute to enhanced risk of DILI development. The polymorphisms 1236T>C, 2677G>T,A and 3435T>C in the ABCB1 gene do not seem to play a role in DILI development in the studied Spanish population. In addition, no participation for the ABCB4 3826A>G polymorphism in DILI susceptibility could be demonstrated. Funding: This work was partially supported by the Spanish Medicine Agency and FIS PS 09/01384. This group belongs to Centro de Investigación Biomédica en Red: Efermedades Hepáticas y Digestivas (CIBERehd). CIBERehd is funded by Instituto de Salud Carlos III.