CONICET | Buscador de Institutos y Recursos Humanos

Acute Intermittent Porphyria (AIP) is a metabolic disease in whichthe mutation in Porphobilinogen deaminase is not enough for themanifestation of the symptoms. We observed that ABCB1 variantswould contribute to its triggering either bioinformatics or experimentally. The aim was to evaluate in silico the influence of variants in NR1I2, a gene that encodes for PXR receptor, regulatorof ABCB1 expression, on AIP onset in relation to porphyrinogenicdrugs. Four NR1I2 SNVs (rs12721613, rs2472677, rs12721607and rs12721608) and the databases gnomAD, PharmGKB, GeneExpression Omnibus, UniProt and GenBank were used. Allele frequencies varied among different geographic regions and ethnicities,reinforcing the relevance of local control group analysis. T allele ofrs2472677 was associated with a phenotype of toxicity, a differential metabolism and efficacy for drugs contraindicated for AIP (Isoniazid, Rifampicin and Efavirenz). Considering models to infer livertoxicity, Rifampicin induced down expression of ABCB1 and 8 CYPsgenes, including CYP3A4, in primary culture of human hepatocytes(GSE139896); Isoniazid caused differential expression of 11 ABCsgenes (27.3% down expressed) and 18 CYPs genes (61.1% downexpressed) in a human liver cancer cell line (GSE168473). No datawere reported for the other variants and the association with toxicityor differential metabolism in the analyzed databases. It is interestingto investigate the role of drugs on gene expression both in drug metabolizing and transport systems, in addition to the allelic and genotypic frequencies of the corresponding variants. Genetic variants ofNR1I2 and their levels of expression could contribute as a possibleactor in the drug-mediated AIP triggering factors. It is therefore ofinterest to continue experimentally exploring variants in this gene incontrols and AIP patients.

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