Mono-methylindoles induce CYP1A genes and inhibit CYP1A1 enzyme activity in human hepatocytes and HepaRG cells

Barbora Vyhlídalová; Karolína Poulíková; Iveta Bartoňková; Kristýna Krasulová; Jan Vančo; Zdeněk Trávníček; Sridhar Mani; Zdeněk Dvořák

doi:10.1016/j.toxlet.2019.06.004

Mono-methylindoles induce CYP1A genes and inhibit CYP1A1 enzyme activity in human hepatocytes and HepaRG cells

Barbora Vyhlídalová, Karolína Poulíková, Iveta Bartoňková, Kristýna Krasulová, Jan Vančo, Zdeněk Trávníček, Sridhar Mani, Zdeněk Dvořák

Oncology

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Mono-methylindoles (MMI) were described as agonists and/or antagonists of the human aryl hydrocarbon receptor (AhR). Here, we investigated the effects of MMI on AhR-CYP1A pathway in human hepatocytes and HepaRG cells derived from human progenitor hepatic cells. All MMI, except of 2-methylindole, strongly induced CYP1A1 and CYP1A2 mRNAs in HepaRG cells. Induction of CYP1A genes was absent in AhR-knock-out HepaRG cells. Consistently, CYP1A1 and CYP1A2 mRNAs and proteins were induced by all MMIs (except 2-methylindole), in human hepatocytes. The enzyme activity of CYP1A1 was inhibited by MMIs in human hepatocytes and LS180 colon cancer cells in a concentration-dependent manner (IC₅₀ values from 1.2 μM to 23.8 μM and from 3.4 μM to 11.4 μM, respectively). Inhibition of CYP1A1 activity by MMI in human liver microsomes was much weaker as compared to that in intact cells. Incubation of parental MMI with human hepatocytes either diminished (4-methylindole, 6-methylindole) or enhanced (7-methylindole) their agonist effects on AhR in AZ-AHR reporter cells. In conclusion, overall effects of MMI on AhR-CYP1A pathway in human cells comprise the induction of CYP1A genes through AhR, the inhibition of CYP1A catalytic activity and possibly the metabolic transformation causing loss or gain of AhR agonist activity of parental compounds.

Original language	English (US)
Pages (from-to)	66-76
Number of pages	11
Journal	Toxicology Letters
Volume	313
DOIs	https://doi.org/10.1016/j.toxlet.2019.06.004
State	Published - Oct 1 2019

Keywords

Aryl hydrocarbon receptor
Entero-hepatic axis
Methylindoles
Microbial catabolites
Tryptophan

ASJC Scopus subject areas

Toxicology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.toxlet.2019.06.004

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@article{93b02790f59f48ebb684b0457f628fa9,

title = "Mono-methylindoles induce CYP1A genes and inhibit CYP1A1 enzyme activity in human hepatocytes and HepaRG cells",

abstract = "Mono-methylindoles (MMI) were described as agonists and/or antagonists of the human aryl hydrocarbon receptor (AhR). Here, we investigated the effects of MMI on AhR-CYP1A pathway in human hepatocytes and HepaRG cells derived from human progenitor hepatic cells. All MMI, except of 2-methylindole, strongly induced CYP1A1 and CYP1A2 mRNAs in HepaRG cells. Induction of CYP1A genes was absent in AhR-knock-out HepaRG cells. Consistently, CYP1A1 and CYP1A2 mRNAs and proteins were induced by all MMIs (except 2-methylindole), in human hepatocytes. The enzyme activity of CYP1A1 was inhibited by MMIs in human hepatocytes and LS180 colon cancer cells in a concentration-dependent manner (IC50 values from 1.2 μM to 23.8 μM and from 3.4 μM to 11.4 μM, respectively). Inhibition of CYP1A1 activity by MMI in human liver microsomes was much weaker as compared to that in intact cells. Incubation of parental MMI with human hepatocytes either diminished (4-methylindole, 6-methylindole) or enhanced (7-methylindole) their agonist effects on AhR in AZ-AHR reporter cells. In conclusion, overall effects of MMI on AhR-CYP1A pathway in human cells comprise the induction of CYP1A genes through AhR, the inhibition of CYP1A catalytic activity and possibly the metabolic transformation causing loss or gain of AhR agonist activity of parental compounds.",

keywords = "Aryl hydrocarbon receptor, Entero-hepatic axis, Methylindoles, Microbial catabolites, Tryptophan",

author = "Barbora Vyhl{\'i}dalov{\'a} and Karol{\'i}na Poul{\'i}kov{\'a} and Iveta Barto{\v n}kov{\'a} and Krist{\'y}na Krasulov{\'a} and Jan Van{\v c}o and Zden{\v e}k Tr{\'a}vn{\'i}{\v c}ek and Sridhar Mani and Zden{\v e}k Dvo{\v r}{\'a}k",

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier B.V.",

year = "2019",

month = oct,

day = "1",

doi = "10.1016/j.toxlet.2019.06.004",

language = "English (US)",

volume = "313",

pages = "66--76",

journal = "Toxicology Letters",

issn = "0378-4274",

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TY - JOUR

T1 - Mono-methylindoles induce CYP1A genes and inhibit CYP1A1 enzyme activity in human hepatocytes and HepaRG cells

AU - Vyhlídalová, Barbora

AU - Poulíková, Karolína

AU - Bartoňková, Iveta

AU - Krasulová, Kristýna

AU - Vančo, Jan

AU - Trávníček, Zdeněk

AU - Mani, Sridhar

AU - Dvořák, Zdeněk

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Mono-methylindoles (MMI) were described as agonists and/or antagonists of the human aryl hydrocarbon receptor (AhR). Here, we investigated the effects of MMI on AhR-CYP1A pathway in human hepatocytes and HepaRG cells derived from human progenitor hepatic cells. All MMI, except of 2-methylindole, strongly induced CYP1A1 and CYP1A2 mRNAs in HepaRG cells. Induction of CYP1A genes was absent in AhR-knock-out HepaRG cells. Consistently, CYP1A1 and CYP1A2 mRNAs and proteins were induced by all MMIs (except 2-methylindole), in human hepatocytes. The enzyme activity of CYP1A1 was inhibited by MMIs in human hepatocytes and LS180 colon cancer cells in a concentration-dependent manner (IC50 values from 1.2 μM to 23.8 μM and from 3.4 μM to 11.4 μM, respectively). Inhibition of CYP1A1 activity by MMI in human liver microsomes was much weaker as compared to that in intact cells. Incubation of parental MMI with human hepatocytes either diminished (4-methylindole, 6-methylindole) or enhanced (7-methylindole) their agonist effects on AhR in AZ-AHR reporter cells. In conclusion, overall effects of MMI on AhR-CYP1A pathway in human cells comprise the induction of CYP1A genes through AhR, the inhibition of CYP1A catalytic activity and possibly the metabolic transformation causing loss or gain of AhR agonist activity of parental compounds.

AB - Mono-methylindoles (MMI) were described as agonists and/or antagonists of the human aryl hydrocarbon receptor (AhR). Here, we investigated the effects of MMI on AhR-CYP1A pathway in human hepatocytes and HepaRG cells derived from human progenitor hepatic cells. All MMI, except of 2-methylindole, strongly induced CYP1A1 and CYP1A2 mRNAs in HepaRG cells. Induction of CYP1A genes was absent in AhR-knock-out HepaRG cells. Consistently, CYP1A1 and CYP1A2 mRNAs and proteins were induced by all MMIs (except 2-methylindole), in human hepatocytes. The enzyme activity of CYP1A1 was inhibited by MMIs in human hepatocytes and LS180 colon cancer cells in a concentration-dependent manner (IC50 values from 1.2 μM to 23.8 μM and from 3.4 μM to 11.4 μM, respectively). Inhibition of CYP1A1 activity by MMI in human liver microsomes was much weaker as compared to that in intact cells. Incubation of parental MMI with human hepatocytes either diminished (4-methylindole, 6-methylindole) or enhanced (7-methylindole) their agonist effects on AhR in AZ-AHR reporter cells. In conclusion, overall effects of MMI on AhR-CYP1A pathway in human cells comprise the induction of CYP1A genes through AhR, the inhibition of CYP1A catalytic activity and possibly the metabolic transformation causing loss or gain of AhR agonist activity of parental compounds.

KW - Aryl hydrocarbon receptor

KW - Entero-hepatic axis

KW - Methylindoles

KW - Microbial catabolites

KW - Tryptophan

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UR - http://www.scopus.com/inward/citedby.url?scp=85067857112&partnerID=8YFLogxK

U2 - 10.1016/j.toxlet.2019.06.004

DO - 10.1016/j.toxlet.2019.06.004

M3 - Article

C2 - 31201936

AN - SCOPUS:85067857112

SN - 0378-4274

VL - 313

SP - 66

EP - 76

JO - Toxicology Letters

JF - Toxicology Letters

ER -

Mono-methylindoles induce CYP1A genes and inhibit CYP1A1 enzyme activity in human hepatocytes and HepaRG cells

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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