Abstract
Hepatitis C virus (HCV) is associated with the development of cirrhosis and hepatocellular carcinoma. We recently found that bovine lactoferrin, a milk protein belonging to the iron transporter family, effectively prevented HCV infection in cultured human hepatocytes (PH5CH8). We tested the hypothesis that lactoferrin inhibits HCV viremia in patients with chronic hepatitis C. Eleven patients with chronic hepatitis C received an 8‐week course of bovine lactoferrin (1.8 or 3.6 g/day). At the end of lactoferrin treatment, a decrease in serum alanine transaminase and HCV RNA concentrations was apparent in 3 (75%) of 4 patients with low pretreatment serum concentrations of HCV RNA. However, 7 patients with high pretreatment concentrations showed no significant changes in these indices. This pilot study suggests that lactoferrin is one potential candidate as an anti‐HCV reagent that may be effective for the treatment of patients with chronic hepatitis.
Keywords: Lactoferrin, Chronic hepatitis, Hepatitis C virus
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REFERENCES
- 1).Choo , Q. L. , Kuo , G. , Weiner , A. J. , Overby , L. R. , Bradley , D. W. and Houghton , M.Isolation of a cDNA clone derived from a blood‐borne non‐A, non‐B viral hepatitis genome . Science , 244 , 359 – 362 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 2).Kuo , G. , Choo , Q. L. , Alter , H. J. , Gitnick , G. L. , Redwker , A. G. , Purcell , R. H. , Miyamura , T. , Dienstag , J. L. , Alter , M. J. , Stevens , C. E. , Tegtmeieer , G. E. , Bonino , F. , Colombo , W. S. , Lee , W. S. , Kuo , C. , Berger , K. , Shuster , J. R. , Overby , L. R. , Bradley , D. W. and Houghton , M.An assay for circulating antibodies to a major etiologic virus of human non‐A, non‐B hepatitis . Science , 244 , 362 – 364 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 3).Ohkoshi , S. , Kojima , H. , Tawaraya , H. , Miyajima , T. , Kamimura , T. , Asakura , H. , Satoh , A. , Hirose , S. , Hijikata , M. , Kato , N. and Shimotohno , K.Prevalence of antibody against non‐A, non‐B hepatitis virus in Japanese patients with hepatocellular carcinoma . Jpn. J. Cancer Res. , 81 , 550 – 553 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4).Saito , I. , Miyamura , T. , Ohbayashi , A. , Harada , H. , Katayama , T. , Kikuchi , S. , Watanabe , Y. , Koi , S. , Onji , M. , Ohta , Y. , Choo , Q. L. , Houghton , M. and Kuo , G.Hepatitis C virus infection is associated with the development of hepatocellular carcinoma . Proc. Natl. Acad. Sci. USA , 87 , 6547 – 6549 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5).Hoofnagle , J. H. , Mullen , K. D. , Jones , D. B. , Rustgi , V. , di Bisceglie , A. , Peters , M. , Waggoner , J. G. , Park , Y. and Jones , E. A.Treatment of chronic non‐A, non‐B hepatitis with recombinant human alpha interferon: a preliminary report . N. Engl. J. Med. , 315 , 1575 – 1578 ( 1986. ). [DOI] [PubMed] [Google Scholar]
- 6).Di Bisceglie , A. M. , Martin , P. , Kassianides , C. , Lisker‐Melman , M. , Murray , L. , Waggoner , J. , Goodman , Z. , Banks , S. M. and Hoofnagle , J. H.Recombinant interferon alpha therapy for chronic hepatitis C: a randomized, double‐blind, placebo‐controlled trial . N. Engl. J. Med. , 321 , 1506 – 1510 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 7).Tine , F. , Margin , S. , Craxi , A. and Pagliaro , L.Interferon for non‐A, non‐B chronic hepatitis: a meta‐analysis of randomized clinical trials . J. Hepatol. , 13 , 192 – 199 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 8).Marcellin , P. , Boyer , N. , Giostra , E. , Degott , C. , Courouce , A. M. , Degos , F. , Coppere , H. , Cales , P. , Couzigou , P. and Benhamou , J.‐P.Recombinant human α‐interferon in patients with chronic non‐A, non‐B hepatitis: a multicenter randomized controlled trial from France . Hepatology , 13 , 393 – 397 ( 1991. ). [PubMed] [Google Scholar]
- 9).Shiratori , Y. , Kato , N. , Yokosuka , O. , Imazeki , F. , Hashimoto , E. , Hayashi , N. , Nakamura , A. , Asada , M. , Kuroda , H. , Tanaka , N. , Arakawa , Y. and Omata , M.for the Tokyo‐Chiba Hepatitis Research Group. Predictors of the efficacy of interferon therapy in chronic hepatitis C virus infection . Gastroenterology , 113 , 558 – 566 ( 1997. ). [DOI] [PubMed] [Google Scholar]
- 10).Kato , N. , Ikeda , M. , Mizutani , T. , Sugiyama , K. , Noguchi , M. , Hirohashi , S. and Shimotohno , K.Replication of hepatitis C virus in cultured non‐neoplastic human hepatocytes . Jpn. J. Cancer Res. , 87 , 787 – 792 ( 1996. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11).Ikeda , M. , Kato , N. , Mizutani , T. , Sugiyama , K. , Tanaka , K. and Shimotohno , K.Analysis of cell tropism of HCV by using in vitro HCV‐infected human lymphocytes and hepatocytes . J. Hepatol. , 27 , 445 – 454 ( 1997. ). [DOI] [PubMed] [Google Scholar]
- 12).Ikeda , M. , Sugiyama , K. , Mizutani , T. , Tanaka , T. , Tanaka , K. , Sekihara , H. , Shimotohno , K. and Kato , N.Human hepatocyte clonal cell lines that support persistent replication of hepatitis C virus . Virus Res. , 56 , 157 – 167 ( 1998. ). [DOI] [PubMed] [Google Scholar]
- 13).Hasegawa , K. , Motsuchi , W. , Tanaka , S. and Dosako , S.Inhibition with lactoferrin of in vitro infection with human herpes virus . Jpn. J. Med. Sci. Biol. , 47 , 73 – 85 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 14).Kirkpatrick , C. H. , Green , I. , Rich , R. R. and Schade , A. L.Inhibition of growth of Candida albicans by iron‐unsaturated lactoferrin: relation to host‐defense mechanisms in chronic mucocutaneous candidiasis . J. Infect. Dis. , 124 , 539 – 544 ( 1971. ). [DOI] [PubMed] [Google Scholar]
- 15).Yamanouchi , K. , Tomita , M. , Giehl , T. J. and Elison , R. T. , III . Antibacterial activity of lactoferrin and a pepsin‐derived lactoferrin peptide fragment . Infect. Immun. , 61 , 719 – 728 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16).Harmsen , M. C. , Swart , P. J. , de Bethune , M.‐P. , Pauwels , R. , De Clercq , E. , The , T. H. and Meijer , D. K. F.Antiviral effects of plasma milk proteins: lactoferrin shows potent activity against both human immunodeficiency virus and human cytomegalovirus replication in vitro . J. Infect. Dis. , 172 , 380 – 388 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 17).Superti , F. , Ammendolia , M. G. , Valent , P. and Seganti , L.Antirotaviral activity of milk protein: lactoferrin prevents rotavirus infection in the enterocyte‐like cell line HT‐29 . Med. Microbiol. Immunol. (Berl.) , 186 , 83 – 91 ( 1997. ). [DOI] [PubMed] [Google Scholar]
- 18).Ikeda , M. , Sugiyama , K. , Tanaka , T. , Tanaka , K. , Sekihara , H. , Shimotohno , K. and Kato , N.Lactoferrin markedly inhibits hepatitis C virus infection in cultured human hepatocytes . Biochem. Biophys. Res. Commun. , 245 , 549 – 553 ( 1998. ). [DOI] [PubMed] [Google Scholar]
- 19).Brock , J.Lactoferrin: a multifunctional immunoregulatory protein ? Immunol. Today , 16 , 417 – 419 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 20).Levay , P. F. and Viljoen , M.Lactoferrin: a general review . Haematologica , 80 , 252 – 267 ( 1995. ). [PubMed] [Google Scholar]
- 21).Yi , M. , Kaneko , S. , Yu , D. Y. and Murakami , S.Hepatitis C virus envelope proteins bind lactoferrin . J. Virol. , 71 , 5997 – 6002 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22).Hagiwara , H. , Hayashi , N. , Mita , E. , Takehara , T. , Kasahara , A. , Fusamoto , H. and Kamada , T.Quantitative analysis of hepatitis C virus RNA in serum during interferon alpha therapy . Gastroenterology , 104 , 877 – 883 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 23).Gil , B. , Quian , C. , Riezu‐Boj , J. I. , Civeira , M. P. and Prieto , J.Hepatic and extrahepatic HCV RNA strands in chronic hepatitis C: different patterns of response to IFN treatment . Hepatology , 18 , 1050 – 1054 ( 1993. ). [PubMed] [Google Scholar]
- 24).Sekine , K. , Watanabe , E. , Nakamura , J. , Takasuka , N. , Kim , D. J. , Asamoto , M. , Krutovskikh , V. , Baba‐Toriyama , H. , Ota , T. , Moore , M. A. , Masuda , M. , Sugimoto , H. , Nishino , H. , Kakizoe , T. and Tsuda , H.Inhibition of azoxymethane‐initiated colon tumor by bovine lactoferrin administration in F344 rats . Jpn. J. Cancer Res. , 88 , 523 – 526 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25).Hutchens , T. W. , Henry , J. F. and Yip , T.‐T.Structurally intact (78‐kDa) forms of maternal lactoferrin purified from urine of preterm infants fed human milk: identification of a trypsin‐like proteolytic cleavage event in vivo that does not result in fragment dissociation . Proc. Natl. Acad. Sci. USA , 88 , 2994 – 2998 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
