RT Journal Article
SR Electronic
T1 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
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 Nakai, Kenya
A1 Tanaka, Hiromasa
A1 Hanada, Kazuhiko
A1 Ogata, Hiroyasu
A1 Suzuki, Fumitaka
A1 Kumada, Hiromitsu
A1 Miyajima, Atsuko
A1 Ishida, Seiichi
A1 Sunouchi, Momoko
A1 Habano, Wataru
A1 Kamikawa, Yuichiro
A1 Kubota, Keiichi
A1 Kita, Junji
A1 Ozawa, Shogo
A1 Ohno, Yasuo
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