Gene Expression Profiling of 1alpha,25(OH)2D3 Treatment in 2D/3D Human Hepatocyte Models Reveals CYP3A4 Induction but Minor Changes in Other Xenobiotic-Metabolizing Genes

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F22%3A10444098" target="_blank" >RIV/00216208:11160/22:10444098 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/75010330:_____/22:00013849 RIV/00216208:11140/22:10444098

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=V0nDexLzhj" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=V0nDexLzhj</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/mnfr.202200070" target="_blank" >10.1002/mnfr.202200070</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Gene Expression Profiling of 1alpha,25(OH)2D3 Treatment in 2D/3D Human Hepatocyte Models Reveals CYP3A4 Induction but Minor Changes in Other Xenobiotic-Metabolizing Genes

Popis výsledku v původním jazyce

Scope: CYP3A4 is the most important drug-metabolizing enzyme regulated via the vitamin D receptor (VDR) in the intestine. However, less is known about VDR in the regulation of CYP3A4 and other drug-metabolizing enzymes in the liver. Methods and Results: This study investigates whether 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) regulates major cytochrome P450 enzymes, selected phase I and II enzymes, and transporters involved in xenobiotic and steroidal endobiotic metabolism in 2D and 3D cultures of human hepatocytes. The authors found that 1alpha,25(OH)2D3 increases hepatic CYP3A4 expression and midazolam 1&apos;-hydroxylation activity in 2D hepatocytes. The results are confirmed in 3D spheroids, where 1alpha,25(OH)2D3 has comparable effect on CYP3A4 mRNA expression as 1alpha-hydroxyvitamin D3, an active vitamin D metabolite. Other regulated genes such as CYP1A2, AKR1C4, SLC10A1, and SLCO4A1 display only mild changes in mRNA levels after 1alpha,25(OH)2D3 treatment in 2D hepatocytes. Expression of other cytochrome P450, phase I and phase II enzyme, or transporter genes are not significantly influenced by 1alpha,25(OH)2D3. Additionally, the effect of VDR activation on CYP3A4 mRNA expression is abolished by natural dietary compound sulforaphane, a common suppressor of pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Conclusion: This study proposes that VDR or vitamin D supplementation is unlikely to significantly influence liver detoxification enzymes apart from CYP3A4.

Název v anglickém jazyce

Gene Expression Profiling of 1alpha,25(OH)2D3 Treatment in 2D/3D Human Hepatocyte Models Reveals CYP3A4 Induction but Minor Changes in Other Xenobiotic-Metabolizing Genes

Popis výsledku anglicky

Scope: CYP3A4 is the most important drug-metabolizing enzyme regulated via the vitamin D receptor (VDR) in the intestine. However, less is known about VDR in the regulation of CYP3A4 and other drug-metabolizing enzymes in the liver. Methods and Results: This study investigates whether 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) regulates major cytochrome P450 enzymes, selected phase I and II enzymes, and transporters involved in xenobiotic and steroidal endobiotic metabolism in 2D and 3D cultures of human hepatocytes. The authors found that 1alpha,25(OH)2D3 increases hepatic CYP3A4 expression and midazolam 1&apos;-hydroxylation activity in 2D hepatocytes. The results are confirmed in 3D spheroids, where 1alpha,25(OH)2D3 has comparable effect on CYP3A4 mRNA expression as 1alpha-hydroxyvitamin D3, an active vitamin D metabolite. Other regulated genes such as CYP1A2, AKR1C4, SLC10A1, and SLCO4A1 display only mild changes in mRNA levels after 1alpha,25(OH)2D3 treatment in 2D hepatocytes. Expression of other cytochrome P450, phase I and phase II enzyme, or transporter genes are not significantly influenced by 1alpha,25(OH)2D3. Additionally, the effect of VDR activation on CYP3A4 mRNA expression is abolished by natural dietary compound sulforaphane, a common suppressor of pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Conclusion: This study proposes that VDR or vitamin D supplementation is unlikely to significantly influence liver detoxification enzymes apart from CYP3A4.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2022

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Molecular Nutrition and Food Research

ISSN

1613-4125

e-ISSN

1613-4133

Svazek periodika

66

Číslo periodika v rámci svazku

9

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

17

Strana od-do

2200070

Kód UT WoS článku

000762216200001

EID výsledku v databázi Scopus

2-s2.0-85125352623