Catecholamines induce an inflammatory response in human hepatocytes.
OBJECTIVE
The liver is an early target organ in sepsis, severe sepsis, and septic shock, contributing to multiple organ failure, and both lipopolysaccharide and gut-derived catecholamines are implicated in the occurrence of hepatocellular dysfunction. Treatment of septic shock involves administration of vasoactive agents such as exogenous catecholamines or vasopressin in order to reestablish blood pressure. As a prelude to clinical application, we tested the hypothesis that catecholamines could modulate the lipopolysaccharide-induced inflammatory response and function in human liver.


METHODS
An in vitro human cell culture study.


METHODS
Research laboratory of an academic institution.


METHODS
Primary human hepatocytes and human hepatoma HepaRG cells.


METHODS
Primary human hepatocytes and human hepatoma HepaRG cells were exposed to lipopolysaccharide to evaluate effects of epinephrine and several other compounds (norepinephrine, dobutamine, dopamine, dopexamine, phenylephrine, clonidine, salbutamol, and vasopressin). Markers of inflammation (interleukin-6, C-reactive protein) and drug metabolism (cytochrome P450 [CYP] 3A4, CYP2B6, CYP1A2, CYP2E1, constitutive androstane receptor, pregnane X receptor) were analyzed.


RESULTS
Transcripts of C-reactive protein and CYP3A4 were strongly increased and depressed respectively after a 24-hr treatment with 10 ng/mL lipopolysaccharide. Co-treatment with either of the catecholamines failed to reverse lipopolysaccharide effects, whereas when added alone, epinephrine, and to a lesser extent norepinephrine, salbutamol, and dobutamine, mimicked lipopolysaccharide effects. Suppression of CYP3A4 implicated beta-adrenergic receptors and was mediated through overproduction of interleukin-6. By contrast, vasopressin did not elicit an inflammatory response or modify CYP3A4 expression.


CONCLUSIONS
Some catecholamines can induce an inflammatory response and exacerbate the hepatic dysfunction observed during sepsis, favoring the idea that catecholamines could alter the biotransformation of drugs metabolized by CYP3A4 and that alternative vasoactive agents, such as vasopressin, merit further investigation in septic shock patients.
Aninat
Caroline
C
INSERM U620, Université de Rennes 1, Rennes, France. caroline.aninat@univ-rennes1.fr
Seguin
Philippe
P
Descheemaeker
Pierre-Néri
PN
Morel
Fabrice
F
Malledant
Yannick
Y
Guillouzo
André
A
D002395:Catecholamines / Q000494:pharmacology*; D002478:Cells, Cultured; D022781:Hepatocytes / Q000187:drug effects* / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D018805:Sepsis / Q000276:immunology
D002395:Catecholamines; D008070:Lipopolysaccharides