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Research ArticleArticle

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

Kenya Nakai, Hiromasa Tanaka, Kazuhiko Hanada, Hiroyasu Ogata, Fumitaka Suzuki, Hiromitsu Kumada, Atsuko Miyajima, Seiichi Ishida, Momoko Sunouchi, Wataru Habano, Yuichiro Kamikawa, Keiichi Kubota, Junji Kita, Shogo Ozawa and Yasuo Ohno
Drug Metabolism and Disposition September 2008, 36 (9) 1786-1793; DOI: https://doi.org/10.1124/dmd.107.020073
Kenya Nakai
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Hiromasa Tanaka
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Kazuhiko Hanada
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Hiroyasu Ogata
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Fumitaka Suzuki
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Hiromitsu Kumada
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Atsuko Miyajima
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Seiichi Ishida
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Momoko Sunouchi
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Wataru Habano
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Yuichiro Kamikawa
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Keiichi Kubota
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Junji Kita
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Shogo Ozawa
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Abstract

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.

Footnotes

  • This study was supported in part by a grant from the Human Science Foundation of Japan, by a Grant-in-Aid from the Ministry of Health, Labor and Welfare, Japan, and by a Grant-in-Aid from the Japanese Ministry of Education, Science and Culture.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.107.020073.

  • ABBREVIATIONS: IL, interleukin; TNF, tumor necrosis factor; HCV, hepatitis C virus; ROS, reactive oxygen species; PCR, polymerase chain reaction; NTCP, Na+-taurocholate-cotransporting peptide; OATP-C, organic anion-transporting peptide-C; OCT1, organic cation transporter 1; MRP, multidrug resistance-associated protein; MDR, multidrug resistance protein; CAR, constitutive androstane receptor; SULT, sulfotransferase; HNF, hepatocyte nuclear factor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; ANOVA, analysis of variance; INR, international normalized ratio.

    • Received December 18, 2007.
    • Accepted May 29, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (9)
Drug Metabolism and Disposition
Vol. 36, Issue 9
1 Sep 2008
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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 Chro…
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Research ArticleArticle

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

Kenya Nakai, Hiromasa Tanaka, Kazuhiko Hanada, Hiroyasu Ogata, Fumitaka Suzuki, Hiromitsu Kumada, Atsuko Miyajima, Seiichi Ishida, Momoko Sunouchi, Wataru Habano, Yuichiro Kamikawa, Keiichi Kubota, Junji Kita, Shogo Ozawa and Yasuo Ohno
Drug Metabolism and Disposition September 1, 2008, 36 (9) 1786-1793; DOI: https://doi.org/10.1124/dmd.107.020073

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Research ArticleArticle

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

Kenya Nakai, Hiromasa Tanaka, Kazuhiko Hanada, Hiroyasu Ogata, Fumitaka Suzuki, Hiromitsu Kumada, Atsuko Miyajima, Seiichi Ishida, Momoko Sunouchi, Wataru Habano, Yuichiro Kamikawa, Keiichi Kubota, Junji Kita, Shogo Ozawa and Yasuo Ohno
Drug Metabolism and Disposition September 1, 2008, 36 (9) 1786-1793; DOI: https://doi.org/10.1124/dmd.107.020073
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