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@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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