PT  - JOURNAL ARTICLE
AU  - Nakai, Kenya
AU  - Tanaka, Hiromasa
AU  - Hanada, Kazuhiko
AU  - Ogata, Hiroyasu
AU  - Suzuki, Fumitaka
AU  - Kumada, Hiromitsu
AU  - Miyajima, Atsuko
AU  - Ishida, Seiichi
AU  - Sunouchi, Momoko
AU  - Habano, Wataru
AU  - Kamikawa, Yuichiro
AU  - Kubota, Keiichi
AU  - Kita, Junji
AU  - Ozawa, Shogo
AU  - Ohno, Yasuo
TI  - Decreased Expression of Cytochromes P450 1A2, 2E1, and 3A4 and Drug Transporters Na<sup>+</sup>-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
AID  - 10.1124/dmd.107.020073
DP  - 2008 Sep 01
TA  - Drug Metabolism and Disposition
PG  - 1786--1793
VI  - 36
IP  - 9
4099  - http://dmd.aspetjournals.org/content/36/9/1786.short
4100  - http://dmd.aspetjournals.org/content/36/9/1786.full
SO  - Drug Metab Dispos2008 Sep 01; 36
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