RT Journal Article SR Electronic T1 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 JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1786 OP 1793 DO 10.1124/dmd.107.020073 VO 36 IS 9 A1 Kenya Nakai A1 Hiromasa Tanaka A1 Kazuhiko Hanada A1 Hiroyasu Ogata A1 Fumitaka Suzuki A1 Hiromitsu Kumada A1 Atsuko Miyajima A1 Seiichi Ishida A1 Momoko Sunouchi A1 Wataru Habano A1 Yuichiro Kamikawa A1 Keiichi Kubota A1 Junji Kita A1 Shogo Ozawa A1 Yasuo Ohno YR 2008 UL http://dmd.aspetjournals.org/content/36/9/1786.abstract AB 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-α 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-α. 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-α 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-α. The American Society for Pharmacology and Experimental Therapeutics