Hepatic Porphyrias and Genetic Variants of ABCG2 Drugs Transporter: Experimental and In Silico Results

ZUCCOLI J; PAGNOTTA P; VARELA, L; MELITO, VA; PARERA, VE; BUZALEH, AM

Bethesda

Simposio; International Porphyrias Sympossium; 2023

United Porphyrias Association

Hepatic Porp hyria s onset is m ediated b y exogenous/endoge nou s factors. Enzyme activity reduction is not enough far Porp hyria m anifest at ion . In Argentina, most common are Acute lntermittent Porphyria (AIP) and Porphyria Cuta n ea Tarda (PCT) . Pr ev iou sl v we investigated th e rol e of ABCBl drugs transporter in AIP and PCTtriggering. NM_004827 .3 :c .34G>A (rs22 311 37) and NIV1_004827 .3 :c.421C>A (rs2231142) variants affect theexpression of A BCG2 , a transporte r of the sam e fami ly of ABC Bl , altering drugs and heme efflux. The aim wasto evaluate the influence of ABCG2 variants in AIP an d 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). AII subjectshave given their informed consent. PCR-RFLP was performed to genotype c.421C>A and direct sequencing farc.34G>A. Far AIP, no significant differences of A allele frequency in either SNVs were found. c.34G>A genotypicfrequencies differed in S-AIP (GG:66.67%, GA :25%, AA :8.33%; pA inheterozygosis (CA) (25.71%, pA werefound for CA, although AA appears in PCT (5%). Haplotype study (c.34G>A/c.421C>A) revealed a risk to developPCT [OR: 4.98 (1.13-21.88), pA frequency of our population was like Americans but far c.421C>A the values were like Africans data.Through PharmGKB database, probability of systemic toxicity and differential drug metabolism were faund inrelation to porphyrinogenic drugs and genetics variants of ABCG2: rs2231137 (2 xenobiotics) and rs2231142(9 xenobiotics). These results reinforce the relevance of advancing towards personal'.zed medicine. _T~egenotyping of an individual, the identification of Hydroxymethylbilane synthetase mutat1on and the tox1c1tyof the different drugs, could lead to a better approach to Porphyria, preventing the onset of symptoms orreducing its severity.