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.
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-alpha showed an increase according to fibrosis stage progression. HepG2 cells and primary hepatocytes of two human individuals were treated with interleukin 1beta, interleukin 6, or tumor necrosis factor-alpha. CYP1A2 and Na(+)-taurocholate-cotransporting polypeptide mRNA levels significantly decreased in HepG2 cells with interleukin 1beta and interleukin 6 treatments. CYP2E1 and organic cation transporter 1 mRNA levels significantly decreased with tumor necrosis factor-alpha 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-alpha.
Division of Pharmacology, National Institute of Health Sciences, Kamiyoga, Tokyo, Japan.
Kenya
K
Nakai
Hiromasa
H
Tanaka
Kazuhiko
K
Hanada
Hiroyasu
H
Ogata
Fumitaka
F
Suzuki
Hiromitsu
H
Kumada
Atsuko
A
Miyajima
Seiichi
S
Ishida
Momoko
M
Sunouchi
Wataru
W
Habano
Yuichiro
Y
Kamikawa
Keiichi
K
Kubota
Junji
J
Kita
Shogo
S
Ozawa
Yasuo
Y
Ohno
D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D019698:Hepatitis C, Chronic / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D027981:Symporters / Q000235:genetics / Q000378:metabolism*
D007527:Isoenzymes; D029363:Organic Anion Transporters, Sodium-Dependent; D027701:Organic Cation Transport Proteins; D012333:RNA, Messenger; D027981:Symporters; C071908:sodium-bile acid cotransporter; D003577:Cytochrome P-450 Enzyme System