Hepatic Porphyrias and genetic variants of ABCG2 drugs transporter: Experimental and in silico results

ZUCCOLI, JOHANNA; PAGNOTTA, PRISCILA; VARELA, LAURA; MELITO, VIVIANA; PARERA, VICTORIA; BUZALEH ANA MARIA

Bethesda, Maryland

Congreso; THE INTERNATIONAL PORPHYRIAS SYMPOSIUM 2023; 2023

American Porphyria Foundation

Hepatic Porphyrias onset is mediated by exogenous/endogenous factors. Enzyme activity reduction is not enough for Porphyria manifestation. In Argentina, most common are Acute Intermittent Porphyria (AIP) and Porphyria Cutanea Tarda (PCT). Previously we investigated the role of ABCB1 drugs transporter in AIP and PCT triggering. NM_004827.3:c.34G>A (rs2231137) and NM_004827.3:c.421C>A (rs2231142) variants affect the expression of ABCG2, a transporter of the same family of ABCB1, altering drugs and heme efflux. The aim was to evaluate the influence of ABCG2 variants in AIP and PCT onset. Four cohorts were included: Control (N=40), AIP: symptomatic at diagnosis (S-AIP) (N=20) or latent (L-AIP) (N=20) and acquired PCT (N=35). All subjects have given their informed consent. PCR-RFLP was performed to genotype c.421C>A and direct sequencing for c.34G>A. For AIP, no significant differences of A allele frequency in either SNVs were found. c.34G>A genotypic frequencies differed in S-AIP (GG:66.67%, GA:25%, AA:8.33%; pA in heterozygosis (CA) (25.71%, pA were found for CA, although AA appears in PCT (5%). Haplotype study (c.34G>A/c.421C>A) revealed a risk to develop PCT [OR: 4.98 (1.13-21.88), pA frequency of our population was like Americans but for c.421C>A the values were like Africans data. Through PharmGKB database, probability of systemic toxicity and differential drug metabolism were found in relation to porphyrinogenic drugs and genetics variants of ABCG2: rs2231137 (2 xenobiotics) and rs2231142 (9 xenobiotics). These results reinforce the relevance of advancing towards personalized medicine. The genotyping of an individual, the identification of Hydroxymethylbilane synthetase mutation and the toxicity of the different drugs, could lead to a better approach to Porphyria, preventing the onset of symptoms or reducing its severity.