• Something wrong with this record ?

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

B. Vyhlídalová, K. Poulíková, I. Bartoňková, K. Krasulová, J. Vančo, Z. Trávníček, S. Mani, Z. Dvořák,

. 2019 ; 313 (-) : 66-76. [pub] 20190612

Language English Country Netherlands

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc19034495

Grant support
P30 DK041296 National Institute of Diabetes and Digestive and Kidney Diseases - United States
R01 CA127231 National Cancer Institute - United States
R01 CA161879 National Cancer Institute - United States
P30 DK020541 National Institute of Diabetes and Digestive and Kidney Diseases - United States
R43 DK105694 National Institute of Diabetes and Digestive and Kidney Diseases - United States
R01 CA222469 National Cancer Institute - United States
P30 CA013330 National Cancer Institute - United States

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.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc19034495
003      
CZ-PrNML
005      
20191010130249.0
007      
ta
008      
191007s2019 ne f 000 0|eng||
009      
AR
024    7_
$a 10.1016/j.toxlet.2019.06.004 $2 doi
035    __
$a (PubMed)31201936
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a ne
100    1_
$a Vyhlídalová, Barbora $u Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71, Olomouc, Czech Republic.
245    10
$a Mono-methylindoles induce CYP1A genes and inhibit CYP1A1 enzyme activity in human hepatocytes and HepaRG cells / $c B. Vyhlídalová, K. Poulíková, I. Bartoňková, K. Krasulová, J. Vančo, Z. Trávníček, S. Mani, Z. Dvořák,
520    9_
$a 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.
650    _2
$a senioři $7 D000368
650    _2
$a transkripční faktory bHLH $x agonisté $x genetika $x metabolismus $7 D051792
650    _2
$a nádorové buněčné linie $7 D045744
650    _2
$a nádory tračníku $x enzymologie $7 D003110
650    _2
$a cytochrom P-450 CYP1A1 $x antagonisté a inhibitory $x biosyntéza $x genetika $7 D019363
650    _2
$a induktory cytochromu P450 $x farmakologie $7 D065693
650    _2
$a inhibitory cytochromu P450 $x farmakologie $7 D065607
650    _2
$a vztah mezi dávkou a účinkem léčiva $7 D004305
650    _2
$a enzymová indukce $7 D004790
650    _2
$a ženské pohlaví $7 D005260
650    _2
$a hepatocyty $x účinky léků $x enzymologie $7 D022781
650    _2
$a lidé $7 D006801
650    _2
$a indoly $x farmakologie $7 D007211
650    _2
$a mužské pohlaví $7 D008297
650    _2
$a jaterní mikrozomy $x účinky léků $x enzymologie $7 D008862
650    _2
$a lidé středního věku $7 D008875
650    _2
$a receptory aromatických uhlovodíků $x agonisté $x genetika $x metabolismus $7 D018336
650    _2
$a mladý dospělý $7 D055815
655    _2
$a časopisecké články $7 D016428
700    1_
$a Poulíková, Karolína $u Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71, Olomouc, Czech Republic.
700    1_
$a Bartoňková, Iveta $u Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71, Olomouc, Czech Republic.
700    1_
$a Krasulová, Kristýna $u Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71, Olomouc, Czech Republic; Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, Slechtitelu 27, 783 71, Olomouc, Czech Republic.
700    1_
$a Vančo, Jan $u Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, Slechtitelu 27, 783 71, Olomouc, Czech Republic.
700    1_
$a Trávníček, Zdeněk $u Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, Slechtitelu 27, 783 71, Olomouc, Czech Republic.
700    1_
$a Mani, Sridhar $u Department of Genetics and Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
700    1_
$a Dvořák, Zdeněk $u Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71, Olomouc, Czech Republic; Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, Slechtitelu 27, 783 71, Olomouc, Czech Republic. Electronic address: zdenek.dvorak@upol.cz.
773    0_
$w MED00004537 $t Toxicology letters $x 1879-3169 $g Roč. 313, č. - (2019), s. 66-76
856    41
$u https://pubmed.ncbi.nlm.nih.gov/31201936 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y a $z 0
990    __
$a 20191007 $b ABA008
991    __
$a 20191010130708 $b ABA008
999    __
$a ok $b bmc $g 1451155 $s 1073045
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2019 $b 313 $c - $d 66-76 $e 20190612 $i 1879-3169 $m Toxicology letters $n Toxicol Lett $x MED00004537
GRA    __
$a P30 DK041296 $p National Institute of Diabetes and Digestive and Kidney Diseases $2 United States
GRA    __
$a R01 CA127231 $p National Cancer Institute $2 United States
GRA    __
$a R01 CA161879 $p National Cancer Institute $2 United States
GRA    __
$a P30 DK020541 $p National Institute of Diabetes and Digestive and Kidney Diseases $2 United States
GRA    __
$a R43 DK105694 $p National Institute of Diabetes and Digestive and Kidney Diseases $2 United States
GRA    __
$a R01 CA222469 $p National Cancer Institute $2 United States
GRA    __
$a P30 CA013330 $p National Cancer Institute $2 United States
LZP    __
$a Pubmed-20191007

Find record

Citation metrics

Archiving options