Acute intermittent porphyria onset: bioinformatic and genetic analysis of porphyrinogenic xenobiotics and drugs transporter system

Autores
Pagnotta, Priscila Ayelén; Melito, Viviana Alicia; Zuccoli, Johanna Romina; Parera, Victoria Estela; Buzaleh, Ana Maria
Año de publicación
2024
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Acute Intermittent Porphyria (AIP) is a metabolic disease in which the mutation in Porphobilinogen deaminase is not enough for the manifestation of the symptoms. Previous experimental results have shown that alternative variants in genes of ABC drug transporter (ABCB1: rs1045642, rs2032582, rs1128503; ABCG2: rs2231137) and NR1I2 gene (rs12721613), regulator of ABC transcription, could be involved in the onset of AIP. The aim was to investigate further the influence of ABCB1, ABCG2 and NR1I2 on AIP onset in relation to porphyrinogenic drugs employing bioinformatics tools. For this purpose, three SNVs of ABCB1 (rs1045642, rs1128503, rs20325822), two SNVs of ABCG2 (rs2231137, rs2231) and four SNVs of NR1I2 (rs12721613, rs2472677, rs12721607, rs12721608) were evaluated using different databases: gnomAD; UniProt; GenBank; PharmGKB, association between genetic variants, drugs and clinical manifestations; Gene Expression Omnibus, expression arrays; PreADMET and SwissADME, to estimate whether drugs are substrates/inhibitors of different transporters. Allele frequencies varied among different geographic regions and ethnicities, reinforcing the relevance of local control group analysis. For NR1I2 gene, T allele of rs2472677 was associated with a phenotype of toxicity, an altered metabolism and/or a different efficacy for drugs contraindicated in AIP (Isoniazid, Rifampicin and Efavirenz). Considering models to infer liver toxicity, Rifampicin induced down expression of ABCB1 and 8 CYP genes, including CYP3A4, in primary culture of human hepatocytes (GSE139896); Isoniazid caused differential expression of 11 ABC genes (27.3% down expressed) and 18 CYP genes (61.1% down expressed) in a human liver cancer cell line (GSE168473). Analyzing Free Wilson’s equations to find possible drugs to replace those insecure for AIP patients, some derivatives of Thiofeno[3,2]pyrimidine would represent therapeutic alternatives to Efavirenz. These derivatives would have a differential action as substrates/inhibitors of ABCB1 transporter and CYP. Associations between non-wild type variants of ABCB1 and ABCG2, drugs contraindicated in AIP and a phenotype of toxicity or alteration of metabolism were also found: rs1045642, rs1128503 and rs1128503 for ABCB1 (13, 2, and 2 xenobiotics, respectively); and rs2231137 and rs2231142 for ABCG2 (2 and 10 xenobiotics, respectively). In conclusion, it was observed that contraindicated drugs for AIP patients are associated with toxicity and a differential metabolism in the presence of the studied variants. In turn, these drugs alter the gene expression of drug metabolizing and transporting systems. Bioinformatics tools are a valuable complement for experimental findings and for exploring new approaches and would be of relevance in personalized medicine and pharmacogenetics, a topic of upmost relevance in the pathophysiology of Hepatic Porphyrias.
Fil: Pagnotta, Priscila Ayelén. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Melito, Viviana Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; Argentina
Fil: Zuccoli, Johanna Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; Argentina
Fil: Parera, Victoria Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; Argentina
Fil: Buzaleh, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; Argentina
International Congress of Porphyrins and Porphyrias
Pamplona
España
International Porphyria Network
Materia
PORPHYRIA
BIOINFORMATIC
PORPHYRINOGENIC XENOBIOTICS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/263962

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network_name_str CONICET Digital (CONICET)
spelling Acute intermittent porphyria onset: bioinformatic and genetic analysis of porphyrinogenic xenobiotics and drugs transporter systemPagnotta, Priscila AyelénMelito, Viviana AliciaZuccoli, Johanna RominaParera, Victoria EstelaBuzaleh, Ana MariaPORPHYRIABIOINFORMATICPORPHYRINOGENIC XENOBIOTICShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Acute Intermittent Porphyria (AIP) is a metabolic disease in which the mutation in Porphobilinogen deaminase is not enough for the manifestation of the symptoms. Previous experimental results have shown that alternative variants in genes of ABC drug transporter (ABCB1: rs1045642, rs2032582, rs1128503; ABCG2: rs2231137) and NR1I2 gene (rs12721613), regulator of ABC transcription, could be involved in the onset of AIP. The aim was to investigate further the influence of ABCB1, ABCG2 and NR1I2 on AIP onset in relation to porphyrinogenic drugs employing bioinformatics tools. For this purpose, three SNVs of ABCB1 (rs1045642, rs1128503, rs20325822), two SNVs of ABCG2 (rs2231137, rs2231) and four SNVs of NR1I2 (rs12721613, rs2472677, rs12721607, rs12721608) were evaluated using different databases: gnomAD; UniProt; GenBank; PharmGKB, association between genetic variants, drugs and clinical manifestations; Gene Expression Omnibus, expression arrays; PreADMET and SwissADME, to estimate whether drugs are substrates/inhibitors of different transporters. Allele frequencies varied among different geographic regions and ethnicities, reinforcing the relevance of local control group analysis. For NR1I2 gene, T allele of rs2472677 was associated with a phenotype of toxicity, an altered metabolism and/or a different efficacy for drugs contraindicated in AIP (Isoniazid, Rifampicin and Efavirenz). Considering models to infer liver toxicity, Rifampicin induced down expression of ABCB1 and 8 CYP genes, including CYP3A4, in primary culture of human hepatocytes (GSE139896); Isoniazid caused differential expression of 11 ABC genes (27.3% down expressed) and 18 CYP genes (61.1% down expressed) in a human liver cancer cell line (GSE168473). Analyzing Free Wilson’s equations to find possible drugs to replace those insecure for AIP patients, some derivatives of Thiofeno[3,2]pyrimidine would represent therapeutic alternatives to Efavirenz. These derivatives would have a differential action as substrates/inhibitors of ABCB1 transporter and CYP. Associations between non-wild type variants of ABCB1 and ABCG2, drugs contraindicated in AIP and a phenotype of toxicity or alteration of metabolism were also found: rs1045642, rs1128503 and rs1128503 for ABCB1 (13, 2, and 2 xenobiotics, respectively); and rs2231137 and rs2231142 for ABCG2 (2 and 10 xenobiotics, respectively). In conclusion, it was observed that contraindicated drugs for AIP patients are associated with toxicity and a differential metabolism in the presence of the studied variants. In turn, these drugs alter the gene expression of drug metabolizing and transporting systems. Bioinformatics tools are a valuable complement for experimental findings and for exploring new approaches and would be of relevance in personalized medicine and pharmacogenetics, a topic of upmost relevance in the pathophysiology of Hepatic Porphyrias.Fil: Pagnotta, Priscila Ayelén. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Melito, Viviana Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Zuccoli, Johanna Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Parera, Victoria Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Buzaleh, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaInternational Congress of Porphyrins and PorphyriasPamplonaEspañaInternational Porphyria NetworkBMJ Publishing Group2024info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectCongresoJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/263962Acute intermittent porphyria onset: bioinformatic and genetic analysis of porphyrinogenic xenobiotics and drugs transporter system; International Congress of Porphyrins and Porphyrias; Pamplona; España; 2024; 5-62054-4774CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://bmjopengastro.bmj.com/content/11/Suppl_1/A2.2Internacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:14:45Zoai:ri.conicet.gov.ar:11336/263962instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:14:46.001CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Acute intermittent porphyria onset: bioinformatic and genetic analysis of porphyrinogenic xenobiotics and drugs transporter system
title Acute intermittent porphyria onset: bioinformatic and genetic analysis of porphyrinogenic xenobiotics and drugs transporter system
spellingShingle Acute intermittent porphyria onset: bioinformatic and genetic analysis of porphyrinogenic xenobiotics and drugs transporter system
Pagnotta, Priscila Ayelén
PORPHYRIA
BIOINFORMATIC
PORPHYRINOGENIC XENOBIOTICS
title_short Acute intermittent porphyria onset: bioinformatic and genetic analysis of porphyrinogenic xenobiotics and drugs transporter system
title_full Acute intermittent porphyria onset: bioinformatic and genetic analysis of porphyrinogenic xenobiotics and drugs transporter system
title_fullStr Acute intermittent porphyria onset: bioinformatic and genetic analysis of porphyrinogenic xenobiotics and drugs transporter system
title_full_unstemmed Acute intermittent porphyria onset: bioinformatic and genetic analysis of porphyrinogenic xenobiotics and drugs transporter system
title_sort Acute intermittent porphyria onset: bioinformatic and genetic analysis of porphyrinogenic xenobiotics and drugs transporter system
dc.creator.none.fl_str_mv Pagnotta, Priscila Ayelén
Melito, Viviana Alicia
Zuccoli, Johanna Romina
Parera, Victoria Estela
Buzaleh, Ana Maria
author Pagnotta, Priscila Ayelén
author_facet Pagnotta, Priscila Ayelén
Melito, Viviana Alicia
Zuccoli, Johanna Romina
Parera, Victoria Estela
Buzaleh, Ana Maria
author_role author
author2 Melito, Viviana Alicia
Zuccoli, Johanna Romina
Parera, Victoria Estela
Buzaleh, Ana Maria
author2_role author
author
author
author
dc.subject.none.fl_str_mv PORPHYRIA
BIOINFORMATIC
PORPHYRINOGENIC XENOBIOTICS
topic PORPHYRIA
BIOINFORMATIC
PORPHYRINOGENIC XENOBIOTICS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Acute Intermittent Porphyria (AIP) is a metabolic disease in which the mutation in Porphobilinogen deaminase is not enough for the manifestation of the symptoms. Previous experimental results have shown that alternative variants in genes of ABC drug transporter (ABCB1: rs1045642, rs2032582, rs1128503; ABCG2: rs2231137) and NR1I2 gene (rs12721613), regulator of ABC transcription, could be involved in the onset of AIP. The aim was to investigate further the influence of ABCB1, ABCG2 and NR1I2 on AIP onset in relation to porphyrinogenic drugs employing bioinformatics tools. For this purpose, three SNVs of ABCB1 (rs1045642, rs1128503, rs20325822), two SNVs of ABCG2 (rs2231137, rs2231) and four SNVs of NR1I2 (rs12721613, rs2472677, rs12721607, rs12721608) were evaluated using different databases: gnomAD; UniProt; GenBank; PharmGKB, association between genetic variants, drugs and clinical manifestations; Gene Expression Omnibus, expression arrays; PreADMET and SwissADME, to estimate whether drugs are substrates/inhibitors of different transporters. Allele frequencies varied among different geographic regions and ethnicities, reinforcing the relevance of local control group analysis. For NR1I2 gene, T allele of rs2472677 was associated with a phenotype of toxicity, an altered metabolism and/or a different efficacy for drugs contraindicated in AIP (Isoniazid, Rifampicin and Efavirenz). Considering models to infer liver toxicity, Rifampicin induced down expression of ABCB1 and 8 CYP genes, including CYP3A4, in primary culture of human hepatocytes (GSE139896); Isoniazid caused differential expression of 11 ABC genes (27.3% down expressed) and 18 CYP genes (61.1% down expressed) in a human liver cancer cell line (GSE168473). Analyzing Free Wilson’s equations to find possible drugs to replace those insecure for AIP patients, some derivatives of Thiofeno[3,2]pyrimidine would represent therapeutic alternatives to Efavirenz. These derivatives would have a differential action as substrates/inhibitors of ABCB1 transporter and CYP. Associations between non-wild type variants of ABCB1 and ABCG2, drugs contraindicated in AIP and a phenotype of toxicity or alteration of metabolism were also found: rs1045642, rs1128503 and rs1128503 for ABCB1 (13, 2, and 2 xenobiotics, respectively); and rs2231137 and rs2231142 for ABCG2 (2 and 10 xenobiotics, respectively). In conclusion, it was observed that contraindicated drugs for AIP patients are associated with toxicity and a differential metabolism in the presence of the studied variants. In turn, these drugs alter the gene expression of drug metabolizing and transporting systems. Bioinformatics tools are a valuable complement for experimental findings and for exploring new approaches and would be of relevance in personalized medicine and pharmacogenetics, a topic of upmost relevance in the pathophysiology of Hepatic Porphyrias.
Fil: Pagnotta, Priscila Ayelén. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Melito, Viviana Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; Argentina
Fil: Zuccoli, Johanna Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; Argentina
Fil: Parera, Victoria Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; Argentina
Fil: Buzaleh, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; Argentina
International Congress of Porphyrins and Porphyrias
Pamplona
España
International Porphyria Network
description Acute Intermittent Porphyria (AIP) is a metabolic disease in which the mutation in Porphobilinogen deaminase is not enough for the manifestation of the symptoms. Previous experimental results have shown that alternative variants in genes of ABC drug transporter (ABCB1: rs1045642, rs2032582, rs1128503; ABCG2: rs2231137) and NR1I2 gene (rs12721613), regulator of ABC transcription, could be involved in the onset of AIP. The aim was to investigate further the influence of ABCB1, ABCG2 and NR1I2 on AIP onset in relation to porphyrinogenic drugs employing bioinformatics tools. For this purpose, three SNVs of ABCB1 (rs1045642, rs1128503, rs20325822), two SNVs of ABCG2 (rs2231137, rs2231) and four SNVs of NR1I2 (rs12721613, rs2472677, rs12721607, rs12721608) were evaluated using different databases: gnomAD; UniProt; GenBank; PharmGKB, association between genetic variants, drugs and clinical manifestations; Gene Expression Omnibus, expression arrays; PreADMET and SwissADME, to estimate whether drugs are substrates/inhibitors of different transporters. Allele frequencies varied among different geographic regions and ethnicities, reinforcing the relevance of local control group analysis. For NR1I2 gene, T allele of rs2472677 was associated with a phenotype of toxicity, an altered metabolism and/or a different efficacy for drugs contraindicated in AIP (Isoniazid, Rifampicin and Efavirenz). Considering models to infer liver toxicity, Rifampicin induced down expression of ABCB1 and 8 CYP genes, including CYP3A4, in primary culture of human hepatocytes (GSE139896); Isoniazid caused differential expression of 11 ABC genes (27.3% down expressed) and 18 CYP genes (61.1% down expressed) in a human liver cancer cell line (GSE168473). Analyzing Free Wilson’s equations to find possible drugs to replace those insecure for AIP patients, some derivatives of Thiofeno[3,2]pyrimidine would represent therapeutic alternatives to Efavirenz. These derivatives would have a differential action as substrates/inhibitors of ABCB1 transporter and CYP. Associations between non-wild type variants of ABCB1 and ABCG2, drugs contraindicated in AIP and a phenotype of toxicity or alteration of metabolism were also found: rs1045642, rs1128503 and rs1128503 for ABCB1 (13, 2, and 2 xenobiotics, respectively); and rs2231137 and rs2231142 for ABCG2 (2 and 10 xenobiotics, respectively). In conclusion, it was observed that contraindicated drugs for AIP patients are associated with toxicity and a differential metabolism in the presence of the studied variants. In turn, these drugs alter the gene expression of drug metabolizing and transporting systems. Bioinformatics tools are a valuable complement for experimental findings and for exploring new approaches and would be of relevance in personalized medicine and pharmacogenetics, a topic of upmost relevance in the pathophysiology of Hepatic Porphyrias.
publishDate 2024
dc.date.none.fl_str_mv 2024
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info:eu-repo/semantics/conferenceObject
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info:ar-repo/semantics/documentoDeConferencia
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dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/263962
Acute intermittent porphyria onset: bioinformatic and genetic analysis of porphyrinogenic xenobiotics and drugs transporter system; International Congress of Porphyrins and Porphyrias; Pamplona; España; 2024; 5-6
2054-4774
CONICET Digital
CONICET
url http://hdl.handle.net/11336/263962
identifier_str_mv Acute intermittent porphyria onset: bioinformatic and genetic analysis of porphyrinogenic xenobiotics and drugs transporter system; International Congress of Porphyrins and Porphyrias; Pamplona; España; 2024; 5-6
2054-4774
CONICET Digital
CONICET
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language eng
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https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
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