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

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)66-76
Number of pages11
JournalToxicology Letters
Volume313
DOIs
StatePublished - Oct 1 2019

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Aryl Hydrocarbon Receptors
Cytochrome P-450 CYP1A1
Enzyme activity
Human Activities
Hepatocytes
Genes
Enzymes
Cytochrome P-450 CYP1A2
Cells
Messenger RNA
Liver
Liver Microsomes
Catalyst activity
Colonic Neoplasms
Inhibitory Concentration 50
Stem Cells
Proteins

Keywords

  • Aryl hydrocarbon receptor
  • Entero-hepatic axis
  • Methylindoles
  • Microbial catabolites
  • Tryptophan

ASJC Scopus subject areas

  • Toxicology

Cite this

Vyhlídalová, B., Poulíková, K., Bartoňková, I., Krasulová, K., Vančo, J., Trávníček, Z., ... Dvořák, Z. (2019). Mono-methylindoles induce CYP1A genes and inhibit CYP1A1 enzyme activity in human hepatocytes and HepaRG cells. Toxicology Letters, 313, 66-76. https://doi.org/10.1016/j.toxlet.2019.06.004

Mono-methylindoles induce CYP1A genes and inhibit CYP1A1 enzyme activity in human hepatocytes and HepaRG cells. / Vyhlídalová, Barbora; Poulíková, Karolína; Bartoňková, Iveta; Krasulová, Kristýna; Vančo, Jan; Trávníček, Zdeněk; Mani, Sridhar; Dvořák, Zdeněk.

In: Toxicology Letters, Vol. 313, 01.10.2019, p. 66-76.

Research output: Contribution to journalArticle

Vyhlídalová, B, Poulíková, K, Bartoňková, I, Krasulová, K, Vančo, J, Trávníček, Z, Mani, S & Dvořák, Z 2019, 'Mono-methylindoles induce CYP1A genes and inhibit CYP1A1 enzyme activity in human hepatocytes and HepaRG cells', Toxicology Letters, vol. 313, pp. 66-76. https://doi.org/10.1016/j.toxlet.2019.06.004
Vyhlídalová B, Poulíková K, Bartoňková I, Krasulová K, Vančo J, Trávníček Z et al. Mono-methylindoles induce CYP1A genes and inhibit CYP1A1 enzyme activity in human hepatocytes and HepaRG cells. Toxicology Letters. 2019 Oct 1;313:66-76. https://doi.org/10.1016/j.toxlet.2019.06.004
Vyhlídalová, Barbora ; Poulíková, Karolína ; Bartoňková, Iveta ; Krasulová, Kristýna ; Vančo, Jan ; Trávníček, Zdeněk ; Mani, Sridhar ; Dvořák, Zdeněk. / Mono-methylindoles induce CYP1A genes and inhibit CYP1A1 enzyme activity in human hepatocytes and HepaRG cells. In: Toxicology Letters. 2019 ; Vol. 313. pp. 66-76.
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AU - Vyhlídalová, Barbora

AU - Poulíková, Karolína

AU - Bartoňková, Iveta

AU - Krasulová, Kristýna

AU - Vančo, Jan

AU - Trávníček, Zdeněk

AU - Mani, Sridhar

AU - Dvořák, Zdeněk

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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.

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