Received for publication December 19, 2007.
Revised May 29, 2008.
Accepted for publication May 29, 2008.

Decreased expression of cytochrome P450s 1A2, 2E1, and 3A4; and drug transporters Na⁺-taurocholate cotransporting polypeptide, organic cation transporter 1, and organic anion-transporting peptide-C correlates with the progression of liver fibrosis in chronic hepatitis C patients

Abstract

Patients with chronic hepatitis C viral infection underwent liver biopsies and laboratory studies for evaluation and to determine subsequent treatment. Changes in status of drug metabolism and disposition may vary with chronic hepatitis C stage and should be assessed. Total RNA was extracted from liver biopsy specimens (n=63) and reverse transcribed to yield cDNA. Relative mRNA levels of drug metabolizing enzymes, transporters, nuclear receptors, and pro-inflammatory cytokines were analyzed with normalization to glyceraldehyde 3-phosphate dehydrogenase expression. mRNAs encoding cytochrome P450s (CYPs) 1A2, 2E1, and 3A4, and drug transporters, Na⁺-taurocholate cotransporting polypeptide, organic anion transporting peptide-C, and organic cation transporter 1 showed remarkable decreases, and tumor necrosis factor- showed an increase according to fibrosis stage progression. HepG2 cells and primary hepatocytes of two human individuals were treated either with interleukin 1, interleukin 6, or tumor necrosis factor-. CYP1A2 and Na⁺-taurocholate cotransporting polypeptide mRNA levels significantly decreased in HepG2 cells with interleukin 1 and interleukin 6 treatments. CYP2E1 and organic cation transporter 1 mRNA levels significantly decreased with tumor necrosis factor- treatment only in HepG2. These results suggested that downregulation of CYP1A2, 2E1, and 3A4, and drug transporters, Na⁺-taurocholate cotransporting polypeptide, organic anion transporting peptide-C, and organic cation transporter 1 manifested in livers of patients with chronic hepatitis C viral infection, was associated, at least in part, with the elevated production of pro-inflammatory cytokines including tumor necrosis factor-.

Key words: CYP expression, cytokines, hepatitis, liver disease, transporters

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