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

. 2019 Oct 01 ; 313 () : 66-76. [epub] 20190612

Jazyk angličtina Země Nizozemsko Médium print-electronic

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/pmid31201936

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

Odkazy

PubMed 31201936
PubMed Central PMC6684055
DOI 10.1016/j.toxlet.2019.06.004
PII: S0378-4274(19)30175-4
Knihovny.cz E-zdroje

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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