CONICET | Buscador de Institutos y Recursos Humanos

Acute Intermittent Porphyria (AIP) is a metabolic disease in which the mutation in Porphobilinogen deaminase is not enough for the manifestation of the symptoms. We observed that ABCB1 variants would 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, regulator of ABCB1 expression, on AIP onset in relation to porphyrinogenic drugs. Four NR1I2 SNVs (rs12721613, rs2472677, rs12721607 and rs12721608) and the databases gnomAD, PharmGKB, Gene Expression Omnibus, UniProt, PreADMET, SwissADME and GenBank were used. Allele frequencies varied among different geographic regions and ethnicities, reinforcing the relevance of local control group analysis. T allele of rs2472677 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 liver toxicity, Rifampicin induced down expression of ABCB1 and 8 CYPs genes, including CYP3A4, in primary culture of human hepatocytes (GSE139896); Isoniazid caused differential expression of 11 ABCs genes (27.3% down expressed) and 18 CYPs genes (61.1% down expressed) in a human liver cancer cell line (GSE168473). No data were reported for the other variants and the association with toxicity or differential metabolism in the analyzed databases. It is interesting to 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 of NR1I2 and their level of expression could contribute as a possible actor in the drug-mediated AIP triggering factors. It is therefore of interest to continue experimentally exploring variants in this gene in controls and AIP patients.

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