Mono-methylindoles induce CYP1A genes and inhibit CYP1A1 enzyme activity in human hepatocytes and HepaRG cells
Jazyk angličtina Země Nizozemsko Médium print-electronic
Typ dokumentu časopisecké články
Grantová podpora
P30 DK041296
NIDDK NIH HHS - United States
R01 CA127231
NCI NIH HHS - United States
R01 CA161879
NCI NIH HHS - United States
P30 DK020541
NIDDK NIH HHS - United States
R43 DK105694
NIDDK NIH HHS - United States
R01 CA222469
NCI NIH HHS - United States
P30 CA013330
NCI NIH HHS - United States
PubMed
31201936
PubMed Central
PMC6684055
DOI
10.1016/j.toxlet.2019.06.004
PII: S0378-4274(19)30175-4
Knihovny.cz E-zdroje
- Klíčová slova
- Aryl hydrocarbon receptor, Entero-hepatic axis, Methylindoles, Microbial catabolites, Tryptophan,
- MeSH
- cytochrom P-450 CYP1A1 antagonisté a inhibitory biosyntéza genetika MeSH
- enzymová indukce MeSH
- hepatocyty účinky léků enzymologie MeSH
- indoly farmakologie MeSH
- induktory cytochromu P450 farmakologie MeSH
- inhibitory cytochromu P450 farmakologie MeSH
- jaterní mikrozomy účinky léků enzymologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- nádorové buněčné linie MeSH
- nádory tračníku enzymologie MeSH
- receptory aromatických uhlovodíků agonisté genetika metabolismus MeSH
- senioři MeSH
- transkripční faktory bHLH agonisté genetika metabolismus MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- AHR protein, human MeSH Prohlížeč
- CYP1A1 protein, human MeSH Prohlížeč
- cytochrom P-450 CYP1A1 MeSH
- indoly MeSH
- induktory cytochromu P450 MeSH
- inhibitory cytochromu P450 MeSH
- receptory aromatických uhlovodíků MeSH
- transkripční faktory bHLH MeSH
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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