Effect of Endocannabinoid Oleamide on Rat and Human Liver
Cytochrome P450 Enzymes in In Vitro and In Vivo Models

J 2018

Effect of Endocannabinoid Oleamide on Rat and Human Liver Cytochrome P450 Enzymes in In Vitro and In Vivo Models

DOVRTĚLOVÁ, Gabriela, Ondřej ZENDULKA, Kristýna NOSKOVÁ, Jan JUŘICA, Ondřej PEŠ et. al.

Basic information

Original name

Effect of Endocannabinoid Oleamide on Rat and Human Liver Cytochrome P450 Enzymes in In Vitro and In Vivo Models

Authors

DOVRTĚLOVÁ, Gabriela (203 Czech Republic, belonging to the institution), Ondřej ZENDULKA (203 Czech Republic, guarantor, belonging to the institution), Kristýna NOSKOVÁ (203 Czech Republic, belonging to the institution), Jan JUŘICA (203 Czech Republic, belonging to the institution), Ondřej PEŠ (203 Czech Republic, belonging to the institution), Jan DUŠEK (203 Czech Republic), Alejandro CARAZO (724 Spain), Iveta ZAPLETALOVÁ (203 Czech Republic), Nataša HLAVÁČOVÁ (703 Slovakia) and Petr PÁVEK (203 Czech Republic)

Edition

Drug Metabolism and Disposition, Bethesda, AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS, 2018, 0090-9556

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30104 Pharmacology and pharmacy

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 3.354

RIV identification code

RIV/00216224:14110/18:00100907

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1124/dmd.117.079582

UT WoS

000439228300016

Keywords in English

cytochrome P450; enzyme inhibitors; liver; hepatic; pharmacokinetics

Abstract

V originále

The endocannabinoid system is important for many physiological and pathological processes, but its role in the regulation of liver cytochromes P450 (CYPs) is still unknown.We studied the influence of the endocannabinoid oleamide on rat and human liver CYPs. Oleamide was administered i.p. to rats at doses of 0.1, 1 and 10 mg/kg/day for 7 days. The content and activity of key CYPs was evaluated in rat liver microsomes. Moreover, its interactions with nuclear receptors regulating CYP genes and serum levels of their ligands (prolactin, corticosterone, and free triiodothyronine) were tested in vitro CYP inhibition assays. Decreased protein levels and metabolic activities of CYP1A2, CYP2B, and CYP2C11 along with a drop in metabolic activity of CYP2D2 were observed in animals treated with oleamide (10 mg/kg/day). The activities of CYP2C6, CYP2A, and CYP3A and the levels of hormones were not altered. In vitro, oleamide exhibited a weak inhibition of rat CYP1A2, CYP2D2, and CYP2C6. The activities of rat CYP2A, CYP2B, CYP2C11, and CYP3A and human CYP1A2, CYP2B6, CYP2C9, and CYP3A4 were not altered. Oleamide did not interact with human pregnane X, constitutive androstane and aryl hydrocarbon receptors in reporter gene experiments and did not regulate their target CYP genes in primary human hepatocytes. Our results indicate that oleamide caused the downregulation of some rat liver CYPs, and hormones are not mediators of this effect. In vitro oleamide inhibits mainly rat CYP2C6 and it is neither an agonist nor antagonist of major human nuclear receptors involved in the regulation of xenobiotic metabolism.

Links

GA16-06106S, research and development project

Name: Vysoce efektivní systém založený na kapilární elektroforéze pro screening inhibitorů beta-sekretázy jako terapeutického cíle pro Alzheimerovu chorobu (Acronym: Alzheimer)

Investor: Czech Science Foundation

LM2015090, research and development project

Name: Český národní uzel Evropské sítě infrastruktur klinického výzkumu (Acronym: CZECRIN)

Investor: Ministry of Education, Youth and Sports of the CR

MUNI/A/0910/2017, interní kód MU

Name: Studium molekulární podstaty vybraných patologických stavů a onemocnění (Acronym: stumopo)

Investor: Masaryk University, Category A

MUNI/A/1132/2017, interní kód MU

Name: Behaviorální psychofarmakologie a farmakokinetika v preklinickém výzkumu léčiv

Investor: Masaryk University, Category A

Citovat

DOVRTĚLOVÁ, Gabriela, Ondřej ZENDULKA, Kristýna NOSKOVÁ, Jan JUŘICA, Ondřej PEŠ, Jan DUŠEK, Alejandro CARAZO, Iveta ZAPLETALOVÁ, Nataša HLAVÁČOVÁ and Petr PÁVEK. Effect of Endocannabinoid Oleamide on Rat and Human Liver Cytochrome P450 Enzymes in In Vitro and In Vivo Models. Drug Metabolism and Disposition. Bethesda: AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS, 2018, vol. 46, No 6, p. 913-923. ISSN 0090-9556. Available from: https://dx.doi.org/10.1124/dmd.117.079582.

@article{1414617,
   author = {Dovrtělová, Gabriela and Zendulka, Ondřej and Nosková, Kristýna and Juřica, Jan and Peš, Ondřej and Dušek, Jan and Carazo, Alejandro and Zapletalová, Iveta and Hlaváčová, Nataša and Pávek, Petr},
   article_location = {Bethesda},
   article_number = {6},
   doi = {http://dx.doi.org/10.1124/dmd.117.079582},
   keywords = {cytochrome P450; enzyme inhibitors; liver; hepatic; pharmacokinetics},
   language = {eng},
   issn = {0090-9556},
   journal = {Drug Metabolism and Disposition},
   title = {Effect of Endocannabinoid Oleamide on Rat and Human Liver Cytochrome P450 Enzymes in In Vitro and In Vivo Models},
   url = {http://dmd.aspetjournals.org/content/early/2018/04/12/dmd.117.079582},
   volume = {46},
   year = {2018}
}

TY  - JOUR
ID  - 1414617
AU  - Dovrtělová, Gabriela - Zendulka, Ondřej - Nosková, Kristýna - Juřica, Jan - Peš, Ondřej - Dušek, Jan - Carazo, Alejandro - Zapletalová, Iveta - Hlaváčová, Nataša - Pávek, Petr
PY  - 2018
TI  - Effect of Endocannabinoid Oleamide on Rat and Human Liver Cytochrome P450 Enzymes in In Vitro and In Vivo Models
JF  - Drug Metabolism and Disposition
VL  - 46
IS  - 6
SP  - 913-923
EP  - 913-923
PB  - AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
SN  - 00909556
KW  - cytochrome P450
KW  - enzyme inhibitors
KW  - liver
KW  - hepatic
KW  - pharmacokinetics
UR  - http://dmd.aspetjournals.org/content/early/2018/04/12/dmd.117.079582
L2  - http://dmd.aspetjournals.org/content/early/2018/04/12/dmd.117.079582
N2  - The endocannabinoid system is important for many physiological and pathological processes, but its role in the regulation of liver cytochromes P450 (CYPs) is still unknown.We studied the influence of the endocannabinoid oleamide on rat and human liver CYPs. Oleamide was administered i.p. to rats at doses of 0.1, 1 and 10 mg/kg/day for 7 days. The content and activity of key CYPs was evaluated in rat liver microsomes. Moreover, its interactions with nuclear receptors regulating CYP genes and serum levels of their ligands (prolactin, corticosterone, and free triiodothyronine) were tested in vitro CYP inhibition assays. Decreased protein levels and metabolic activities of CYP1A2, CYP2B, and CYP2C11 along with a drop in metabolic activity of CYP2D2 were observed in animals treated with oleamide (10 mg/kg/day). The activities of CYP2C6, CYP2A, and CYP3A and the levels of hormones were not altered. In vitro, oleamide exhibited a weak inhibition of rat CYP1A2, CYP2D2, and CYP2C6. The activities of rat CYP2A, CYP2B, CYP2C11, and CYP3A and human CYP1A2, CYP2B6, CYP2C9, and CYP3A4 were not altered. Oleamide did not interact with human pregnane X, constitutive androstane and aryl hydrocarbon receptors in reporter gene experiments and did not regulate their target CYP genes in primary human hepatocytes. Our results indicate that oleamide caused the downregulation of some rat liver CYPs, and hormones are not mediators of this effect. In vitro oleamide inhibits mainly rat CYP2C6 and it is neither an agonist nor antagonist of major human nuclear receptors involved in the regulation of xenobiotic metabolism.
ER  -

DOVRTĚLOVÁ, Gabriela, Ondřej ZENDULKA, Kristýna NOSKOVÁ, Jan JUŘICA, Ondřej PEŠ, Jan DUŠEK, Alejandro CARAZO, Iveta ZAPLETALOVÁ, Nataša HLAVÁČOVÁ and Petr PÁVEK. Effect of Endocannabinoid Oleamide on Rat and Human Liver Cytochrome P450 Enzymes in In Vitro and In Vivo Models. \textit{Drug Metabolism and Disposition}. Bethesda: AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS, 2018, vol.~46, No~6, p.~913-923. ISSN~0090-9556. Available from: https://dx.doi.org/10.1124/dmd.117.079582.

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