Functional impact of cytochrome P450 3A (CYP3A) missense variants in cattle

Abstract Cytochrome P450 3A is the most important CYP subfamily in humans, and CYP3A4/CYP3A5 genetic variants contribute to inter-individual variability in drug metabolism. However, no information is available for bovine CYP3A (bCYP3A). Here we described bCYP3A missense single nucleotide variants (S...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Mery Giantin, Minna Rahnasto-Rilla, Roberta Tolosi, Lorena Lucatello, Marianna Pauletto, Giorgia Guerra, Francesca Pezzato, Rosa M. Lopparelli, Roberta Merlanti, Paolo Carnier, Francesca Capolongo, Paavo Honkakoski, Mauro Dacasto
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c25ec162a21642f68798b8d5ca6a8b2b
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:c25ec162a21642f68798b8d5ca6a8b2b
record_format	dspace
spelling	oai:doaj.org-article:c25ec162a21642f68798b8d5ca6a8b2b2021-12-02T13:35:12ZFunctional impact of cytochrome P450 3A (CYP3A) missense variants in cattle10.1038/s41598-019-56271-82045-2322https://doaj.org/article/c25ec162a21642f68798b8d5ca6a8b2b2019-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-56271-8https://doaj.org/toc/2045-2322Abstract Cytochrome P450 3A is the most important CYP subfamily in humans, and CYP3A4/CYP3A5 genetic variants contribute to inter-individual variability in drug metabolism. However, no information is available for bovine CYP3A (bCYP3A). Here we described bCYP3A missense single nucleotide variants (SNVs) and evaluated their functional effects. CYP3A28, CYP3A38 and CYP3A48 missense SNVs were identified in 300 bulls of Piedmontese breed through targeted sequencing. Wild-type and mutant bCYP3A cDNAs were cloned and expressed in V79 cells. CYP3A-dependent oxidative metabolism of testosterone (TST) and nifedipine (NIF) was assessed by LC-MS/MS. Finally, SNVs functional impact on TST hydroxylation was measured ex vivo in liver microsomes from individually genotyped animals. Thirteen missense SNVs were identified and validated. Five variants showed differences in CYP3A catalytic activity: three CYP3A28 SNVs reduced TST 6β-hydroxylation; one CYP3A38 variant increased TST 16β-hydroxylation, while a CYP3A48 SNV showed enhanced NIF oxidation. Individuals homozygous for rs384467435 SNV showed a reduced TST 6β-hydroxylation. Molecular modelling showed that most of SNVs were distal to CYP3A active site, suggesting indirect effects on the catalytic activity. Collectively, these findings demonstrate the importance of pharmacogenetics studies in veterinary species and suggest bCYP3A genotype variation might affect the fate of xenobiotics in food-producing species such as cattle.Mery GiantinMinna Rahnasto-RillaRoberta TolosiLorena LucatelloMarianna PaulettoGiorgia GuerraFrancesca PezzatoRosa M. LopparelliRoberta MerlantiPaolo CarnierFrancesca CapolongoPaavo HonkakoskiMauro DacastoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-15 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mery Giantin Minna Rahnasto-Rilla Roberta Tolosi Lorena Lucatello Marianna Pauletto Giorgia Guerra Francesca Pezzato Rosa M. Lopparelli Roberta Merlanti Paolo Carnier Francesca Capolongo Paavo Honkakoski Mauro Dacasto Functional impact of cytochrome P450 3A (CYP3A) missense variants in cattle
description	Abstract Cytochrome P450 3A is the most important CYP subfamily in humans, and CYP3A4/CYP3A5 genetic variants contribute to inter-individual variability in drug metabolism. However, no information is available for bovine CYP3A (bCYP3A). Here we described bCYP3A missense single nucleotide variants (SNVs) and evaluated their functional effects. CYP3A28, CYP3A38 and CYP3A48 missense SNVs were identified in 300 bulls of Piedmontese breed through targeted sequencing. Wild-type and mutant bCYP3A cDNAs were cloned and expressed in V79 cells. CYP3A-dependent oxidative metabolism of testosterone (TST) and nifedipine (NIF) was assessed by LC-MS/MS. Finally, SNVs functional impact on TST hydroxylation was measured ex vivo in liver microsomes from individually genotyped animals. Thirteen missense SNVs were identified and validated. Five variants showed differences in CYP3A catalytic activity: three CYP3A28 SNVs reduced TST 6β-hydroxylation; one CYP3A38 variant increased TST 16β-hydroxylation, while a CYP3A48 SNV showed enhanced NIF oxidation. Individuals homozygous for rs384467435 SNV showed a reduced TST 6β-hydroxylation. Molecular modelling showed that most of SNVs were distal to CYP3A active site, suggesting indirect effects on the catalytic activity. Collectively, these findings demonstrate the importance of pharmacogenetics studies in veterinary species and suggest bCYP3A genotype variation might affect the fate of xenobiotics in food-producing species such as cattle.
format	article
author	Mery Giantin Minna Rahnasto-Rilla Roberta Tolosi Lorena Lucatello Marianna Pauletto Giorgia Guerra Francesca Pezzato Rosa M. Lopparelli Roberta Merlanti Paolo Carnier Francesca Capolongo Paavo Honkakoski Mauro Dacasto
author_facet	Mery Giantin Minna Rahnasto-Rilla Roberta Tolosi Lorena Lucatello Marianna Pauletto Giorgia Guerra Francesca Pezzato Rosa M. Lopparelli Roberta Merlanti Paolo Carnier Francesca Capolongo Paavo Honkakoski Mauro Dacasto
author_sort	Mery Giantin
title	Functional impact of cytochrome P450 3A (CYP3A) missense variants in cattle
title_short	Functional impact of cytochrome P450 3A (CYP3A) missense variants in cattle
title_full	Functional impact of cytochrome P450 3A (CYP3A) missense variants in cattle
title_fullStr	Functional impact of cytochrome P450 3A (CYP3A) missense variants in cattle
title_full_unstemmed	Functional impact of cytochrome P450 3A (CYP3A) missense variants in cattle
title_sort	functional impact of cytochrome p450 3a (cyp3a) missense variants in cattle
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/c25ec162a21642f68798b8d5ca6a8b2b
work_keys_str_mv	AT merygiantin functionalimpactofcytochromep4503acyp3amissensevariantsincattle AT minnarahnastorilla functionalimpactofcytochromep4503acyp3amissensevariantsincattle AT robertatolosi functionalimpactofcytochromep4503acyp3amissensevariantsincattle AT lorenalucatello functionalimpactofcytochromep4503acyp3amissensevariantsincattle AT mariannapauletto functionalimpactofcytochromep4503acyp3amissensevariantsincattle AT giorgiaguerra functionalimpactofcytochromep4503acyp3amissensevariantsincattle AT francescapezzato functionalimpactofcytochromep4503acyp3amissensevariantsincattle AT rosamlopparelli functionalimpactofcytochromep4503acyp3amissensevariantsincattle AT robertamerlanti functionalimpactofcytochromep4503acyp3amissensevariantsincattle AT paolocarnier functionalimpactofcytochromep4503acyp3amissensevariantsincattle AT francescacapolongo functionalimpactofcytochromep4503acyp3amissensevariantsincattle AT paavohonkakoski functionalimpactofcytochromep4503acyp3amissensevariantsincattle AT maurodacasto functionalimpactofcytochromep4503acyp3amissensevariantsincattle
_version_	1718392699029028864

Functional impact of cytochrome P450 3A (CYP3A) missense variants in cattle

Ejemplares similares