Activation of MAPKs influences the expression of drug-metabolizing enzymes in primary human hepatocytes.
We examined the effects of model activators of mitogen-activated protein kinases (MAPKs) on basal and rifampicin-, phenobarbital- and dioxin-inducible expression of phase I and phase II biotransformation enzymes in primary human hepatocytes. Cells were treated for 24 h with sorbitol (SOR), anisomycin (ANI) and epidermal growth factor (EGF) in the presence or absence of inducers. The levels of CYP1A1, CYP1A2, CYP2B6, CYP3A4, UGT1A1, UGT2B17, SULT1A1, SULT2A1, SULT1B2, GSTA1, GSTA2 mRNAs were determined. SOR and EGF inhibited the expression of the tested genes, while ANI had no effect. We conclude that MAPKs play important role in the transcriptional regulation of drug-metabolizing enzymes.
Bachleda
Petr
P
2nd Department of Surgery, University Hospital Olomouc, I. P. Pavlova 6, 775 20 Olomouc, Czech Republic.
Vrzal
Radim
R
Dvorák
Zdenek
Z
D000841:Anisomycin / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D004147:Dioxins / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D010634:Phenobarbital / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D012293:Rifampin / Q000494:pharmacology; D013012:Sorbitol / Q000494:pharmacology; D015238:Sulfotransferases / Q000378:metabolism
D004147:Dioxins; D020536:Enzyme Activators; D012333:RNA, Messenger; D013012:Sorbitol; D004815:Epidermal Growth Factor; D000841:Anisomycin; D001189:Aryl Hydrocarbon Hydroxylases; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D048049:Extracellular Signal-Regulated MAP Kinases; D015238:Sulfotransferases; D012293:Rifampin; D010634:Phenobarbital