QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.107.020073v1 36/9/1786    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Nakai, K. Articles by Ohno, Y. PubMed PubMed Citation Articles by Nakai, K. Articles by Ohno, Y.

Decreased Expression of Cytochromes P450 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

Division of Pharmacology (K.N., H.T., A.M., S.I., M.S., S.O.) and Deputy Director General (Y.O.), National Institute of Health Sciences, Kamiyoga, Setagaya-ku, Tokyo, Japan; Department of Biopharmaceutics, Meiji Pharmaceutical University, Noshio, Kiyose, Tokyo, Japan (K.N., H.T., K.H., H.O.); Department of Hepatology, Toranomon Hospital, Toranomon, Minato-ku, Tokyo, Japan (F.S., H.K.); Department of Pharmacodynamics and Molecular Genetics, Faculty of Pharmaceutical Sciences, Iwate Medical University, Nishitokuta, Yahabacho, Shiwa-gun, Iwate, Japan (W.H., S.O.); Department of Pharmacology and Surgery Division (Y.K.) and Second Department of Surgery (K.K., J.K.), Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan

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 proinflammatory cytokines were analyzed with normalization to glyceraldehyde 3-phosphate dehydrogenase expression. mRNAs encoding cytochromes P450 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 with interleukin 1β, interleukin 6, or tumor necrosis factor-. CYP1A2 and Na⁺-taurocholate-cotransporting polypeptide mRNA levels significantly decreased in HepG2 cells with interleukin 1β 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 down-regulation 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 proinflammatory cytokines, including tumor necrosis factor-.