Regulation of Cytochrome P450 2a5 by Artemisia capillaris and 6,7-Dimethylesculetin in Mouse Hepatocytes

Jaundice is a potentially fatal condition resulting from elevated serum bilirubin levels. For centuries, herbal remedies containing Artemisia capillaris Thunb. including the compound 6,7-dimethylesculetin (DE) have been used in Asia to prevent and treat jaundice in neonates. DE activates an importan...

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Autores principales:	Sangsoo Daniel Kim, Larry Morgan, Elyse Hargreaves, Xiaoying Zhang, Zhihui Jiang, Monica Antenos, Ben Li, Gordon M. Kirby
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	Artemisia capillaris thunb cytochrome P450 mouse gene regulation liver jaundice Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/6af15ebff21245f88c8e4e68639529a6
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spelling	oai:doaj.org-article:6af15ebff21245f88c8e4e68639529a62021-11-22T06:34:25ZRegulation of Cytochrome P450 2a5 by Artemisia capillaris and 6,7-Dimethylesculetin in Mouse Hepatocytes1663-981210.3389/fphar.2021.730416https://doaj.org/article/6af15ebff21245f88c8e4e68639529a62021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.730416/fullhttps://doaj.org/toc/1663-9812Jaundice is a potentially fatal condition resulting from elevated serum bilirubin levels. For centuries, herbal remedies containing Artemisia capillaris Thunb. including the compound 6,7-dimethylesculetin (DE) have been used in Asia to prevent and treat jaundice in neonates. DE activates an important regulator of bilirubin metabolism, the constitutive androstane receptor (CAR), and increases bilirubin clearance. In addition, murine cytochrome P450 2a5 (Cyp2a5) is known to be involved in the oxidative metabolism of bilirubin. Moreover, treatment of mice with phenobarbital, a known inducer of both CAR and Cyp2a5, increases expression of Cyp2a5 suggesting a potential relationship between CAR and Cyp2a5 expression. The aim of this study is to investigate the influence of Artemisia capillaris and DE on the expression and regulatory control of Cyp2a5 and the potential involvement of CAR. Treatment of mouse hepatocytes in primary culture with DE (50 μM) significant increased Cyp2a5 mRNA and protein levels. In mice, Artemisia capillaris and DE treatment also increased levels of hepatic Cyp2a5 protein. Luciferase reporter assays showed that CAR increases Cyp2a5 gene transcription through a CAR response element in the Cyp2a5 gene promoter. Moreover, DE caused nuclear translocation of CAR in primary mouse hepatocytes and increased Cyp2a5 transcription in the presence of CAR. These results identify a potential CAR-mediated mechanism by which DE regulates Cyp2a5 gene expression and suggests that DE may enhance bilirubin clearance by increasing Cyp2a5 levels. Understanding this process could provide an opportunity for the development of novel therapies for neonatal and other forms of jaundice.Sangsoo Daniel KimLarry MorganElyse HargreavesXiaoying ZhangXiaoying ZhangZhihui JiangMonica AntenosBen LiGordon M. KirbyFrontiers Media S.A.articleArtemisia capillaris thunbcytochrome P450mousegene regulationliverjaundiceTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Artemisia capillaris thunb cytochrome P450 mouse gene regulation liver jaundice Therapeutics. Pharmacology RM1-950
spellingShingle	Artemisia capillaris thunb cytochrome P450 mouse gene regulation liver jaundice Therapeutics. Pharmacology RM1-950 Sangsoo Daniel Kim Larry Morgan Elyse Hargreaves Xiaoying Zhang Xiaoying Zhang Zhihui Jiang Monica Antenos Ben Li Gordon M. Kirby Regulation of Cytochrome P450 2a5 by Artemisia capillaris and 6,7-Dimethylesculetin in Mouse Hepatocytes
description	Jaundice is a potentially fatal condition resulting from elevated serum bilirubin levels. For centuries, herbal remedies containing Artemisia capillaris Thunb. including the compound 6,7-dimethylesculetin (DE) have been used in Asia to prevent and treat jaundice in neonates. DE activates an important regulator of bilirubin metabolism, the constitutive androstane receptor (CAR), and increases bilirubin clearance. In addition, murine cytochrome P450 2a5 (Cyp2a5) is known to be involved in the oxidative metabolism of bilirubin. Moreover, treatment of mice with phenobarbital, a known inducer of both CAR and Cyp2a5, increases expression of Cyp2a5 suggesting a potential relationship between CAR and Cyp2a5 expression. The aim of this study is to investigate the influence of Artemisia capillaris and DE on the expression and regulatory control of Cyp2a5 and the potential involvement of CAR. Treatment of mouse hepatocytes in primary culture with DE (50 μM) significant increased Cyp2a5 mRNA and protein levels. In mice, Artemisia capillaris and DE treatment also increased levels of hepatic Cyp2a5 protein. Luciferase reporter assays showed that CAR increases Cyp2a5 gene transcription through a CAR response element in the Cyp2a5 gene promoter. Moreover, DE caused nuclear translocation of CAR in primary mouse hepatocytes and increased Cyp2a5 transcription in the presence of CAR. These results identify a potential CAR-mediated mechanism by which DE regulates Cyp2a5 gene expression and suggests that DE may enhance bilirubin clearance by increasing Cyp2a5 levels. Understanding this process could provide an opportunity for the development of novel therapies for neonatal and other forms of jaundice.
format	article
author	Sangsoo Daniel Kim Larry Morgan Elyse Hargreaves Xiaoying Zhang Xiaoying Zhang Zhihui Jiang Monica Antenos Ben Li Gordon M. Kirby
author_facet	Sangsoo Daniel Kim Larry Morgan Elyse Hargreaves Xiaoying Zhang Xiaoying Zhang Zhihui Jiang Monica Antenos Ben Li Gordon M. Kirby
author_sort	Sangsoo Daniel Kim
title	Regulation of Cytochrome P450 2a5 by Artemisia capillaris and 6,7-Dimethylesculetin in Mouse Hepatocytes
title_short	Regulation of Cytochrome P450 2a5 by Artemisia capillaris and 6,7-Dimethylesculetin in Mouse Hepatocytes
title_full	Regulation of Cytochrome P450 2a5 by Artemisia capillaris and 6,7-Dimethylesculetin in Mouse Hepatocytes
title_fullStr	Regulation of Cytochrome P450 2a5 by Artemisia capillaris and 6,7-Dimethylesculetin in Mouse Hepatocytes
title_full_unstemmed	Regulation of Cytochrome P450 2a5 by Artemisia capillaris and 6,7-Dimethylesculetin in Mouse Hepatocytes
title_sort	regulation of cytochrome p450 2a5 by artemisia capillaris and 6,7-dimethylesculetin in mouse hepatocytes
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/6af15ebff21245f88c8e4e68639529a6
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Regulation of Cytochrome P450 2a5 by Artemisia capillaris and 6,7-Dimethylesculetin in Mouse Hepatocytes

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