Abstract
The purpose of this study was to assess the impact of interferon-α2b (IFN-α2b) on the expression of various drug-metabolizing enzymes and transporters in freshly prepared co-cultures (parenchymal and non-parenchymal cells) of human primary hepatocytes. At therapeutically relevant concentrations (from 1000 to 3000 IU/mL), IFN-α2b up-regulated STAT1 (signal transducer and activator of transcription factor 1) mRNA expression. Conversely, three cytochrome P450s (CYP1A2, CYP2B6, CYP2E1), a UDP-glucuronosyltransferase (UGT2B7), a sulphotransferase (SULT1A1) and organic anion transporter (OAT2) were significantly down-regulated (~50%; P < 0.05). Western blot analysis of CYP1A2, UGT2B7 and OAT2 protein supported the mRNA data. Two peroxisome proliferator activator receptor alpha (PPARα)-controlled genes (pyruvate dehydrogenase kinase 4 and adipose differentiation-related protein), CYP3A4 and multidrug resistance-associated protein 2 were significantly up-regulated (up to 223%; P < 0.05). On the other hand, SULT2A1, carboxylesterase 2, organic anion transporting peptide (OATP1B1, OATP1B3, OATP2B1), organic cation transporter 1, P-glycoprotein and breast cancer resistance protein mRNA expression was not significantly affected. Western blot analysis of CYP3A4 supported the mRNA data also. The present results demonstrated complex interactions between IFN-α2b and hepatocytes and the observed down-regulation of CYP1A2, OAT2 and UGT2B7 is consistent with reports of drug interactions between IFN-α2b and drugs such as theophylline, clozapine and gemfibrozil.
MeSH terms
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism
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Antiviral Agents / pharmacology*
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Aryl Hydrocarbon Hydroxylases / genetics
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Aryl Hydrocarbon Hydroxylases / metabolism
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Biological Transport / drug effects
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Carboxylic Ester Hydrolases / genetics
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Carboxylic Ester Hydrolases / metabolism
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Cells, Cultured
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Cytochrome P-450 CYP1A2 / genetics
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Cytochrome P-450 CYP1A2 / metabolism
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Cytochrome P-450 CYP2B6
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Cytochrome P-450 Enzyme System / genetics
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Cytochrome P-450 Enzyme System / metabolism
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Cytochrome P450 Family 2
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Down-Regulation / drug effects
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Gene Expression Regulation, Enzymologic / drug effects*
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Glucuronosyltransferase / genetics
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Glucuronosyltransferase / metabolism
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Hepatocytes / drug effects*
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Hepatocytes / enzymology
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Humans
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Interferon alpha-2
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Interferon-alpha / pharmacology*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Metabolic Detoxication, Phase I / genetics
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Metabolic Detoxication, Phase II / genetics
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Organic Anion Transporters, Sodium-Independent / genetics
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Organic Anion Transporters, Sodium-Independent / metabolism
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Oxidoreductases, N-Demethylating / genetics
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Oxidoreductases, N-Demethylating / metabolism
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Perilipin-2
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Protein Kinases / genetics
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Protein Kinases / metabolism
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RNA, Messenger / metabolism
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Recombinant Proteins
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STAT1 Transcription Factor / genetics
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STAT1 Transcription Factor / metabolism
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Sulfotransferases / genetics
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Sulfotransferases / metabolism
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Up-Regulation / drug effects
Substances
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ATP-Binding Cassette Transporters
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Antiviral Agents
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Interferon alpha-2
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Interferon-alpha
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Membrane Proteins
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Organic Anion Transporters, Sodium-Independent
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PLIN2 protein, human
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Perilipin-2
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RNA, Messenger
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Recombinant Proteins
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SLC22A7 protein, human
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STAT1 Transcription Factor
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STAT1 protein, human
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Cytochrome P-450 Enzyme System
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Aryl Hydrocarbon Hydroxylases
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CYP1A2 protein, human
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CYP2B6 protein, human
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CYP2F1 protein, human
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Cytochrome P-450 CYP1A2
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Cytochrome P-450 CYP2B6
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Cytochrome P450 Family 2
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Oxidoreductases, N-Demethylating
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UGT2B7 protein, human
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Glucuronosyltransferase
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Protein Kinases
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pyruvate dehydrogenase kinase 4
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Sulfotransferases
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Carboxylic Ester Hydrolases