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Investigating the Correlation between Genotypes and Hepatic Protein Expression of CYP2C9, CYP2C19, CYP2D6, and CYP3A5 Using Postmortem Tissue from a Danish Population.
Pedersen, Kata W; Andersen, Jeppe D; Hansen, Jakob; Børsting, Claus; Banner, Jytte; Hasselstrøm, Jørgen B; Jornil, Jakob R.
Afiliação
  • Pedersen KW; Department of Forensic Medicine, Aarhus University, Aarhus, Denmark (K.W.P., J.H., J.B.H., J.R.J.); and Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark (J.D.A., C.B., J.B.).
  • Andersen JD; Department of Forensic Medicine, Aarhus University, Aarhus, Denmark (K.W.P., J.H., J.B.H., J.R.J.); and Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark (J.D.A., C.B., J.B.).
  • Hansen J; Department of Forensic Medicine, Aarhus University, Aarhus, Denmark (K.W.P., J.H., J.B.H., J.R.J.); and Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark (J.D.A., C.B., J.B.).
  • Børsting C; Department of Forensic Medicine, Aarhus University, Aarhus, Denmark (K.W.P., J.H., J.B.H., J.R.J.); and Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark (J.D.A., C.B., J.B.).
  • Banner J; Department of Forensic Medicine, Aarhus University, Aarhus, Denmark (K.W.P., J.H., J.B.H., J.R.J.); and Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark (J.D.A., C.B., J.B.).
  • Hasselstrøm JB; Department of Forensic Medicine, Aarhus University, Aarhus, Denmark (K.W.P., J.H., J.B.H., J.R.J.); and Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark (J.D.A., C.B., J.B.).
  • Jornil JR; Department of Forensic Medicine, Aarhus University, Aarhus, Denmark (K.W.P., J.H., J.B.H., J.R.J.); and Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark (J.D.A., C.B., J.B.) jjor@forens.au.dk.
Drug Metab Dispos ; 52(9): 975-980, 2024 Aug 14.
Article em En | MEDLINE | ID: mdl-38906700
ABSTRACT
The cytochrome P450 (CYP) family of enzymes plays a central role in the metabolism of many drugs. CYP genes are highly polymorphic, which is known to affect protein levels, but for some low frequent CYP genotypes the correlation between genotype and CYP protein expression is less established. In this study, we determined the CYP2C9, CYP2C19, CYP2D6, and CYP3A5 genotypes of 250 Danish individuals included in a postmortem study. For 116 of the individuals, the hepatic CYP protein levels were investigated by a proteomics approach. Overall, we found the postmortem genetic and proteomic data to be in agreement with those of other studies performed on fresh hepatic tissue, showing the usability of postmortem hepatic tissue for this type of investigation. For less investigated genotypes, we could corroborate previously found

results:

1) statistically significantly lower levels of hepatic CYP2C9 protein in individuals carrying the CYP2C9*3 variant compared with individuals with two wild type (wt) alleles; 2) comparable levels of CYP2C19 in CYP2C19*2/*17 and CYP2C19*1/*2 individuals; 3) reduced CYP2D6 protein levels in heterozygous individuals with the CYP2D6*3, CYP2D6*4, and CYP2D6*5 gene deletion variants; and 4) significantly lower levels of CYP3A5 protein in CYP3A5*3 homozygous individuals compared with individuals who were heterozygous for the CYP3A5*3 allele or homozygous individuals for the wt alleles. In conclusion, the use of postmortem tissue significantly increases the access to human specimens for research purposes, and postmortem proteomics can be used to investigate the link between CYP genotypes and hepatic protein expression. SIGNIFICANCE STATEMENT In tissue samples from a large postmortem cohort (n = 250) we determined the CYP2C9, CYP2C19, CYP2D6, and CYP3A5 genotypes. Hepatic CYP protein levels were investigated in 116 individuals using a proteomics approach. For common genotypes, we found results similar to previous knowledge, pointing toward the usability of postmortem tissue. For the less investigated genotypes, we were able to corroborate genotype/protein expression correlations. It is a novel approach to use a large postmortem cohort to investigate genetic/protein expression correlations.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Citocromo P-450 CYP2D6 / Citocromo P-450 CYP3A / Citocromo P-450 CYP2C9 / Citocromo P-450 CYP2C19 / Genótipo / Fígado Limite: Adult / Aged / Female / Humans / Male / Middle aged País/Região como assunto: Europa Idioma: En Revista: Drug Metab Dispos Assunto da revista: FARMACOLOGIA Ano de publicação: 2024 Tipo de documento: Article País de publicação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Citocromo P-450 CYP2D6 / Citocromo P-450 CYP3A / Citocromo P-450 CYP2C9 / Citocromo P-450 CYP2C19 / Genótipo / Fígado Limite: Adult / Aged / Female / Humans / Male / Middle aged País/Região como assunto: Europa Idioma: En Revista: Drug Metab Dispos Assunto da revista: FARMACOLOGIA Ano de publicação: 2024 Tipo de documento: Article País de publicação: Estados Unidos