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Abstracts

Hepatitis B

ABSTRACTS

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Thymosin alpha-1.

Ancell CD, Phipps J, Young L. Nova Factor, Memphis, TN, USA.

Am J Health Syst Pharm. 2001 May 15;58(10):879-85; quiz 886-8.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of thymosin alpha-1 (TA1) are reviewed. TA1 is a synthetic polypeptide. The drug is in Phase III trials for the treatment of hepatitis C and in Phase II trials for hepatitis B. Additional possible indications are malignant melanoma, hepatocellular carcinoma, drug-resistant tuberculosis, and DiGeorge's syndrome. TA1 is thought to modulate the immune system by augmenting T-cell function. TA1 may affect thymocytes by stimulating their differentiation or by converting them to active T cells. TA1 is rapidly absorbed, achieving peak serum concentrations within two hours. Blood levels return to baseline within 24 hours, and the serum half-life is approximately 2 hours. TA1's efficacy in hepatitis B has been evaluated in 195 patients in four clinical trials. One study found hepatitis B virus (HBV) DNA clearance at six months in 9 of 17 patients receiving TA1, compared with 10 of 16 patients treated with interferon alfa-2b (IFN-alpha 2b) and 4 of 15 historical controls. An open-label trial found HBV DNA clearance in 53% of patients at six months. A randomized, controlled trial found HBV DNA clearance in 40.6% and 25.6% of patients treated with TA1 for 6 and 12 months, respectively, compared with 9.4% of untreated controls. Efficacy for hepatitis C has been evaluated in 162 patients in three clinical trials. In one trial, the number of patients who achieved normal serum alanine aminotransferase (ALT) levels did not differ significantly between TA1 and placebo. In the other two trials, combination TA1 and IFN-alpha 2b was compared with IFN-alpha 2b alone. One trial found a normal serum ALT level at six months in 71% of patients receiving combination therapy, versus 35% of patients receiving IFN-alpha 2b alone. Hepatitis C virus RNA clearance occurred in 65% of patients treated with combination therapy and 29% of patients treated with IFN-alpha 2b alone. The third trial, comparing combination TA1 and IFN-alpha 2b with IFN-alpha 2b alone and with placebo, found normalization of ALT levels at six months in 37.1% of patients receiving combination therapy, 16.2% of patients receiving IFN-alpha 2b alone, and 2.7% of patients receiving placebo. TA1 is well tolerated. Most studies observed only local irritation at the injection site. For hepatitis B and C, TA1 1.6 mg (900 micrograms/m2) should be administered subcutaneously twice a week. Clinical trials of TA1 for chronic hepatitis B or C have had mixed results. TA1 may be useful as monotherapy for hepatitis B or in combination with IFN-alpha 2b for hepatitis C, but its effects on morbidity and mortality remain to be seen.

A comparative trial of standard or high-dose S subunit recombinant hepatitis B vaccine versus a vaccine containing S subunit, pre-S1, and pre-S2 particles for revaccination of healthy adult nonresponders.

Bertino JS Jr, Tirrell P, Greenberg RN, Keyserling HL, Poland GA, Gump D, Kumar ML, Ramsey K. Bassett Healthcare, Cooperstown, New York 13326-1394, USA.

J Infect Dis. 1997 Mar;175(3):678-81.

The efficacy of 10-microg and 40-microg hepatitis B vaccines was compared with that of an investigational vaccine containing pre-S1, pre-S2, and S subunit particles (mixed particle vaccine) in inducing protective anti-hepatitis B surface antigen (anti-HBs) concentrations in 46 otherwise healthy persons who previously did not develop measurable levels of antibodies to at least one complete course of vaccine. A statistically significant difference was seen in the percentage of subjects who developed protective levels of anti-HBs (> or = 10 mIU/mL) with three 40-microg doses of S subunit vaccine versus the other groups. One hundred percent of the 40-microg dose group developed protective anti-HBs titers. No difference in adverse effects was noted.

Resistance of hepatitis B virus to antiviral drugs: current aspects and directions for future investigation.

Delaney WE 4th, Locarnini S, Shaw T. Victorian Infectious Diseases Reference Laboratory, North Melbourne, Australia. wdelaney@gilead.com

Antivir Chem Chemother. 2001 Jan;12(1):1-35.

Despite the existence of vaccines, chronic hepatitis B virus (HBV) infection remains a major health problem worldwide. Interferon therapy successfully controls infection in only a small percentage of chronically infected individuals. The recent approval of the nucleoside analogue lamivudine for the treatment of chronic HBV infection has ushered in a new era of antiviral therapy. While lamivudine is highly effective at controlling viral infection short-term, prolonged therapy has been associated with an increasing incidence of viral resistance. Thus, it appears that lamivudine alone will not be sufficient to control chronic viral infection in the majority of individuals. In addition to lamivudine, several new nucleoside and nucleotide analogues that show promising antihepadnaviral activity are in various stages of development. Lamivudine resistance has been found to confer cross-resistance to some of these compounds and it is likely that resistance to newer antivirals may also develop during prolonged use. Drug resistance therefore poses a major threat to nucleoside analogue-based therapies for chronic HBV infection. Fortunately, combination chemotherapy (antiviral therapy with two or more agents) can minimize the chance that resistance will develop and can be expected to achieve sustained reductions in viral load, provided that suitable combinations of agents are chosen. Here we review the basis of drug resistance in HBV, with emphasis on aspects that are likely to affect drug choice in future.

Nonresponders to hepatitis B vaccine can present envelope particles to T lymphocytes.

Desombere I, Hauser P, Rossau R, Paradijs J, Leroux-Roels G. Department of Clinical Chemistry, University of Ghent, Belgium.

J Immunol. 1995 Jan 15;154(2):520-9.

The mechanisms causing nonresponsiveness to hepatitis B surface Ag (HBsAg) vaccines in humans remain largely unknown. The increased incidence of nonresponsiveness in subjects with HLA-DR3 or -DR7 haplotype suggests that immune response mechanisms governed by genes of the MHC are involved. It is conceivable that APC of nonresponders are defective in the presentation of HBsAg because they are unable to adequately take up, process, or present this Ag. To examine this hypothesis we have used PBMC from nonresponders to present recombinant particles containing S or PreS2-S sequences to HBsAg-specific T cell lines from haplo-identical responder vaccinees. The proliferative response of these lines was used to evaluate the efficacy of Ag presentation. Unfractionated PBMC from five DR2+ and six DR7+ nonresponders did not proliferate to HBsAg in vitro, whereas they vigorously proliferated upon stimulation with tetanus toxoid, thus ruling out the presence of a generalized immunodeficiency. All DR2(15)+ nonresponders were able to present hepatitis B envelope Ag to HBsAg-specific, DR1501-restricted T cells. PBMC from six DR7+ nonresponders were all able to present HBsAg to DR07-restricted T cell lines and PBMC from three DPw4+ nonresponders were able to present HBsAg to DP0402-restricted T cell lines. Additional experiments showed that PBMC from two nonresponders presented HBsAg equally well and sometimes better than PBMC from two partially HLA-matched high responders. We conclude that HLA-DR2+, -DR7+, and -DPw4+ nonresponder vaccinees are able to take up, process and present HBsAg to allogeneic, haplo-identical T cell lines in vitro.

HLA tissue types in nonresponders to hepatitis B vaccine.

Durupinar B, Okten G. Department of Microbiology and Clinical Microbiology, Ondokuz Mayis University Faculty of Medicine, Samsun, Turkiye.

Indian J Pediatr. 1996 May-Jun;63(3):369-73.

Genetic factors are implicated in the response of normal subjects to hepatitis B vaccine. In order to investigate the immunogenetic factors associated with nonresponsiveness to hepatitis B vaccine, 93 health care workers were vaccinated with hepatitis B vaccine. Initial nonresponders (antibody not detected or antibody detected but < 10 mlU/ml) were revaccinated. Only 12 (12.9%) of the 93 health care workers, who had anti-HBs levels of 10 mlU/ml or less after revaccination were defined as absolute nonresponders. HLA typing were performed in these 12 nonresponders, Anti-HBs levels were determined by ELISA method in mlU/ml units. HLA-A,B,C,DR, and DQ typing was performed using the microcytotoxicity test. The HLA-A10 (pc less than 0.01) and CW4 (pc less than 0.006) were decreased whereas DR7 (pc less than 0.09) was increased in nonresponders. Although our initial results suggest the importance of genetic modulation of responsiveness to hepatitis B vaccine, a formal demonstration of the mode of inheritance of unresponsiveness to hepatitis B vaccine and the explanation of the role of genes in this matter will require further studies of families.

Current pharmacotherapy for hepatitis B infection.

Galan MV, Boyce D, Gordon SC. Division of Gastroenterology-Hepatology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.

Expert Opin Pharmacother. 2001 Aug;2(8):1289-98.

Chronic infection with the hepatitis B virus (HBV) affects 350 million people worldwide, or approximately 5% of the global population, and commonly results in cirrhosis and hepatocellular carcinoma. Until recently, the only available treatment was injectable interferon alpha and response rates were suboptimal. Moreover, this expensive and toxic therapy had little applicability in the endemic regions of the world, i.e., Asia and Africa. The realisation that orally available nucleoside and nucleotide agents may effectively control this infection opened a new era in the management of chronic hepatitis B. Oral lamivudine recently became approved for treatment of hepatitis B worldwide. It is free of significant toxicity, improves liver histology and rapidly diminishes HBV DNA levels; lamivudine is expected to become the first-line therapy of choice. Nevertheless, the consistent emergence of lamivudine-resistant variants mandates the need to develop additional therapeutic agents. Adefovir dipivoxil, a nucleotide, and entecavir, a nucleoside agent, are promising new drugs that might eventually be used in combination with lamivudine and therefore reduce the incidence of drug resistance. There is a critical need to advance the research of hepatitis B antiviral agents so that effective combination therapies can become widely available.

Advances in antiviral agents for hepatitis B virus.

Gumina G, Song GY, Chu CK. Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens.

Antivir Chem Chemother. 2001;12 Suppl 1:93-117.

Hepatitis B virus (HBV) is the third most common disease after venereal diseases and chickenpox. HBV currently infects 2 billion people in the world, of which 350 million are chronic carriers. At least 1 million chronically infected individuals die each year due to HBV-related diseases, especially cirrhosis and liver cancer. The greatest concern about the diffusion of this virus is in endemic regions in central and southern Africa, South-East Asia and South America, where neonatal exposure results in high mortality rates. Anti-HBV therapy has made important progresses in the last decade, with two approved drugs and a number of other potent agents in the pharmaceutical industry pipeline. Nevertheless, resistance and viral rebound are still major issues in devising a winning strategy, and there is a continuous need of developing new active compounds, as well as therapeutic protocols based on combination therapy and a prophylactic approach. This review will summarize the latest advances in anti-HBV therapy, with particular regard to the latest clinical data on the most significant anti-HBV agents. Issues such as viral resistance and combination therapy will be highlighted.

[Clinical aspects and therapy of viral hepatitis] [Article in German]

Lammert F, Busch N, Matern S. Medizinische Klinik III, Universitatsklinikum der RWTH Aachen.

Chirurg. 2000 Apr;71(4):381-8.

Acute hepatitis can be caused by the enterically spread hepatitis A and E viruses and the parenterally spread hepatitis B, C or D viruses. The clinical features of acute viral hepatitis are similar among the five viruses and include non-specific symptoms and icterus. In general, a specific therapy is not necessary, but patients with fulminant hepatitis may require liver transplantation. For acute hepatitis C, the effect of interferon-alpha on the risk of chronicity is evaluated in clinical trials. Chronic hepatitis is defined as inflammatory reaction in the liver that continues without improvement for at least 6 months after infection with hepatitis B, C or D viruses. Hepatitis B resolves in more than 90% of the patients, but chronic infection can lead to liver cirrhosis and hepatocellular carcinoma. Chronic hepatitis C is an insidious disease, because early diagnosis is missed easily due to asymptomatic presentation and about 70% of infected patients develop chronic hepatitis. The benefits of interferon-alpha and/or nucleoside analogues have been proven in recent clinical trials that show sustained responses in more than a third of all patients with chronic viral hepatitis. The future treatment of chronic viral hepatitis will likely include immunomodulation and gene therapy.

Trace elements and chronic liver diseases.

Loguercio C, De Girolamo V, Federico A, Feng SL, Cataldi V, Del Vecchio Blanco C, Gialanella G. Cattedra di Gastroenterologia, Seconda Universita di Napoli, Italia.

J Trace Elem Med Biol. 1997 Nov;11(3):158-61.

The relationships between chronic liver diseases and trace element (TE) contents are debated. Particularly, no defined data are available about the TE levels in viral liver disease patients with or without malnutrition. In this study we evaluated blood and plasma levels of various trace elements in patients with HCV-related chronic liver disease, at different stages of liver damage (8 patients with chronic hepatitis and 32 with liver cirrhosis) with or without malnutrition. We also studied 10 healthy volunteers as control group. We found that cirrhotic subjects had a significant decrease of blood levels of Zn and Se, independently on the nutritional status, whereas plasma levels of Fe were significantly reduced only in malnourished cirrhotic patients. Our data indicate that liver impairment is the main cause of the blood decrease of Se and Zn levels in patients with non alcoholic liver disease, whereas the malnutrition affects Fe levels only.

Chronic hepatitis B virus infection: treatment strategies for the next millennium.

Malik AH, Lee WM. Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas 75390-9151, USA.

Ann Intern Med. 2000 May 2;132(9):723-31.

Chronic hepatitis B virus (HBV) infection is a leading cause of cirrhosis and hepatocellular carcinoma worldwide. Its prevalence approaches 10% in hyperendemic areas, such as southeast Asia, China, and Africa. Although chronic HBV infection is seen less frequently in North America and Europe, an estimated 1.25 million persons in the United States are infected. In the past decade, revolutionary strides have been made toward the treatment of chronic HBV infection. Interferon-alpha was once the only available therapy but has recently been joined by the nucleoside analogues, the most extensively studied of which is lamivudine. Interferon therapy continues to have a role in the treatment of a carefully selected group of patients. Lamivudine therapy, which has less stringent selection criteria, suppresses HBV DNA in almost all treated patients: Seventeen percent to 33% experience loss of hepatitis B e antigen, and 53% to 56% have a histologic response. Extended lamivudine treatment leads to the development of a specific lamivudine-resistant virus with base-pair substitutions at the YMDD locus of the DNA polymerase. Newer nucleoside analogues and other immunomodulator therapies are being investigated. In the future, combination therapy with different classes of agents may yield improved response rates and delay the development of resistance.

The management of chronic hepatitis B infection.

Matthews GV, Nelson MR. Department of HIV Medicine, Chelsea & Westminster Hospital, London, UK.

Int J STD AIDS. 2001 Jun;12(6):353-7.

Chronic hepatitis B infection is frequently diagnosed within the genitourinary clinic setting with sexual transmission the commonest route of acquisition in the United Kingdom. Only 3--5% of adults who contract acute hepatitis B will progress to chronic infection, and these individuals can be identified by the presence of hepatitis B surface antigen (HBsAg) in the bloodstream 6 months after infection. Individuals at highest risk of long-term complications such as cirrhosis and hepatocellular carcinoma, carry HBeAg and have high levels of circulating hepatitis B virus (HBV) deoxyribonucleic acid (DNA). Therapy should be targeted towards this group of patients. Two forms of therapy are now licensed for use in chronic hepatitis B infection: interferon-alpha and lamivudine. Seroconversion occurs in 30--40% of patients treated with interferon and treatment is often limited by toxicity. Lamivudine is well tolerated with seroconversion rates of 15--20% at one year, rising with increasing duration of therapy. Long-term monotherapy is limited however by the development of resistance mutations and combination nucleoside therapy is likely to become the treatment of choice in the future. Patients with chronic hepatitis B should be counselled regarding transmission, partner vaccination and alcohol intake and co-infection with other hepatitis viruses should be excluded.

Does hepatitis B virus (HBV) genotype influence the clinical outcome of HBV infection?

Mayerat C, Mantegani A, Frei PC. Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland.

J Viral Hepat. 1999 Jul;6(4):299-304.

Between 5 and 10% of adults infected with the hepatitis B virus (HBV) develop a chronic infection lasting longer than 6 months, which may lead to advanced liver disease. HBV can be classified into six genotypic families: A, B, C, D, E and F, but only genotypes A and D are significantly represented in western Europe, where they account for some 90% of cases of infection with HBV. In the present study, we investigated a possible association between HBV genotype A or D and clinical outcome of the infection. We compared the prevalence of these genotypes in a group of patients with chronic active hepatitis to that of a group with acute resolving hepatitis. In patients with chronic active hepatitis, genotype A was found in 28 of 35 patients and genotype D in only four. The remaining three patients were infected with genotype non-A, non-D. In contrast, genotype D was found in 24 of 30 patients with acute hepatitis, whilst genotype A was found in only three patients of this group. Three were infected with genotype non-A, non-D. Our results show a clear association between genotype A and chronic outcome (Ficher's exact test: two-sided P-value, P < 0.0001). They suggest that HBV genotypes may play a role in the virus-host relationship. Possible mechanisms for such a role are discussed.

Additive antiviral effects of lamivudine and alpha-interferon in chronic hepatitis B infection.

Mutimer D, Dowling D, Cane P, Ratcliffe D, Tang H, O'Donnell K, Shaw J, Elias E, Pillay D. Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, Birmingham, UK. david.mutimer@university-b.wmids.nhs.uk

Antivir Ther. 2000 Dec;5(4):273-7.

alpha-Interferon has limited efficacy against chronic hepatitis B virus (HBV) infection. Nucleoside analogues may confer greater benefits, however, it is likely that combination therapies will be required for effective control of this infection. We investigated the antiviral effect of lamivudine and interferon therapy in eight patients with high HBV-DNA levels. Six patients received lamivudine/interferon combination therapy followed, after a 6-month drug-free period, with lamivudine monotherapy. Mean HBV viral load (copies/ml) reduction was significantly greater after 4 months of combination therapy (4.3 x 10(3)) compared to an equivalent period of lamivudine monotherapy (2.9 x 10(2)) (P=0.03). Two patients were given 6 months of lamivudine/interferon combination therapy followed immediately by lamivudine monotherapy. Cessation of interferon in these patients led to a rapid 1-2 log10 increase in HBV viral load. These findings suggest that alpha-interferon has a direct antiviral effect on chronic HBV infection, which may be additive to, or synergistic with lamivudine.

Reactive oxygen species and nitric oxide in viral diseases.

Peterhans E. Institute of Veterinary Virology, University of Berne, Switzerland. peterhans@ivv.unibe.ch

Biol Trace Elem Res. 1997 Jan;56(1):107-16.

Metabolites derived from superoxide (O2.-) and nitric oxide (NO.) play an important role in antimicrobial and antitumoral defense, but may also harm the host. Low levels of such metabolites can also facilitate viral replication because of their mitogenic effects on cells. Most viruses grow better in proliferating cells, and indeed, many viruses induce in their host cell changes similar to those seen early after treatment with mitogenic lectins. Influenza and paramyxo-viruses activate in phagocytes in the generation of superoxide by a mechanism involving the interaction between the viral surface glycoproteins and the phagocyte's plasma membrane. Interestingly, viruses that activate this host defense mechanism are toxic when injected in the bloodstream of animals. Mice infected with influenza virus undergo oxidative stress. In addition, a wide array of cytokines are formed in the lung, contributing to the systemic effects of influenza. Oxidative stress is seen also in chronic viral infections, such as AIDS and viral hepatitis. Oxidant production in viral hepatitis may contribute to the emergence of hepatocellular carcinoma, a tumor seen in patients after years of chronic inflammation of the liver. Antioxidants and agents that downregulate proinflammatory cytokines and lipid mediators may be a useful complement to specific antiviral drugs in the therapy of viral diseases.

Regulative potential of glutamine--relation to glutathione metabolism.

Roth E, Oehler R, Manhart N, Exner R, Wessner B, Strasser E, Spittler A. Department of Surgery, Research Laboratories, Vienna, Austria. e.roth@akh-wien.ac.at

Nutrition. 2002 Mar;18(3):217-21.

Glutamine (GLN) is the most abundant free amino acid (AA) in the human body. Under GLN-free conditions, which can be obtained when cells are cultivated in vitro, tissue cells cannot grow. Therefore, when classifying GLN as a "non-essential" AA, one must consider that in the human body GLN is synthesized from essential AAs and is continuously delivered from skeletal muscle to other organs. It is fascinating that a relatively simple AA like GLN can stimulate a large variety of cellular reactions. GLN stimulates not only the growth of cells but also the expression of surface antigens, the formation of cytokines, and the synthesis of heat shock proteins. Further, a GLN deficiency leads to a cell cycle arrest in G(0) to G(1) and reduces apoptosis. Interestingly, many of these biological activities also are associated with the cellular reduced oxygen potential, which depends mainly on the ratio of reduced to oxidized glutathione. Experimental animal studies have shown that the administration of GLN increases tissue concentrations of reduced glutathione. This review describes the relation of GLN to reduced glutathione metabolism and discusses the alteration of reduced glutathione metabolism under a variety of clinical conditions such as reperfusion injury, myocardial infarction, respiratory insufficiency, cancer, diabetes, liver disease, and clinical protein catabolism.

Stimulatory effect of silibinin on the DNA synthesis in partially hepatectomized rat livers: non-response in hepatoma and other malign cell lines.

Sonnenbichler, J., Goldberg, M., Hane, L. et al.

Biochem. Pharmacol. 1986 Feb 1; 35(3): 538 41.

No Abstract available.

Biochemical bases of the pharmacological action of the flavonoid silymarin and of its structural isomer silibinin.

Valenzuela A, Garrido A. Unidad de Bioquimica Farmacologica y Lipidos, Universidad de Chile, Santiago.

Biol Res. 1994;27(2):105-12.

The flavonoid silymarin and one its structural components, silibinin, have been well characterized as hepato-protective substances. However, little is known about the biochemical mechanisms of action of these substances. This review deals with recent investigations to elucidate the molecular action of the flavonoid. Three levels of action have been proposed for silymarin in experimental animals: a) as an antioxidant, by scavenging prooxidant free radicals and by increasing the intracellular concentration of the tripeptide glutathione; b) regulatory action of the cellular membrane permeability and increase of its stability against xenobiotic injury; c) at the nuclear expression, by increasing the synthesis of ribosomal RNA by stimulating DNA polymerase I and by exerting a steroid-like regulatory action on DNA transcription. The specific hepatoprotective action of silibinin against the toxicity of ethanol, phenylhydrazine and acetaminophen is also discussed. It is suggested that the biochemical effects observed for the flavonoid in experimental models may settle the basis for understanding the pharmacological action of silymarin and silibinin.

Vitamin E improves the aminotransferase status of patients suffering from viral hepatitis C: a randomized, double-blind, placebo-controlled study.

von Herbay A, Stahl W, Niederau C, Sies H. Department of Internal Medicine (GI-Unit), Heinrich-Heine-Universitat Dusseldorf, Germany.

Free Radic Res. 1997 Dec;27(6):599-605.

Vitamin E has been shown to protect against liver damage induced by oxidative stress in animal experiments. Based on our previous findings of diminished vitamin E levels in patients suffering from viral hepatitis, we treated 23 hepatitis C patients refractory to alpha-interferon therapy with high doses of vitamin E (2 x 400 IU RRR-alpha-tocopherol/day) for 12 weeks. Study design: pro-spective randomized double-blind crossover design. Clinical parameters including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined for monitoring the disease state, in parallel vitamin E plasma levels and plasma lipids were determined. The plasma levels of the alpha-tocopherol were increased about 2-fold in all 23 patients. In 11 of 23 patients the clinical parameters indicative of liver damage were improved during the phase of vitamin E treatment (48% responders). ALT levels in responders were lowered by 46% and AST levels were lowered by 35% after 12 weeks of vitamin E treatment. Cessation of vitamin E treatment was followed by a rapid relapse of ALT and AST elevation, whereas retreatment led to a reproducible ALT decrease by 45% and AST decrease of 37% after a 6 months followup. Since vitamin E is non-toxic even at elevated doses ingested over extended periods, we suggest the treatment of patients refractory to alpha-interferon therapy suffering from hepatitis C with vitamin E as a supportive therapy.

[Alanyl-glutamine dipeptides protected the liver function by increasing the hepatic glutathione] [Article in Chinese]

Yu J, Jiang Z, Li D, Yang N, Bai M. PUMC Hospital, CAMS and PUMC, Beijing 100730.

Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 1998 Apr;20(2):103-8.

OBJECTIVE: Glutathione (GSH) is a major antioxidant which protects hepatic tissues from free radical injury. Alanyl-Glutamine (ALA-GLN) proved to be a precursor of GSH synthesis, was used to investigate the relationship to GSH biosynthesis which may be effective for hepatic protection. METHODS: 20 male Wistar rats were randomly divided into two groups receiving standard parenteral nutrition (STD) supplemented with or without ALA-GLN for 7 days. At 5th day 5-fluorouracil (5-FU) was injected peritoneally, the blood samples for GSH, GSSG, ALT (sGPT), AKP and TBilli tests were measured after 4-8 h. RESULTS: The concentration measurements were significantly different in ALA-GLN group compared with STD animals in serum GLN (687.3 +/- 49.8) vs (504.9 +/- 38.6) mumol/L, P < 0.05), serum GSH (14.37 +/- 5.16) vs (7.08 +/- 3.16) mumol/L, P < 0.01) and in liver GSH content (6.86 +/- 2.46) vs (4.38 +/- 1.63) mumol/g liver tissue, P < 0.05). Rats in ALA-GLN group have lesser elevations in hepatic enzymes after 5-FU administration. CONCLUSIONS: The supplemented nutrition ALA-GLN protected the liver function through increasing the glutathione biosynthesis and preserving the glutathione stores of hepatic tissue.

Glutamine: a precursor of glutathione and its effect on liver.

Yu JC, Jiang ZM, Li DM. Department of Surgery, Peking Union Medical College Hospital Chinese Academy of Medical Sciences, 1 Shuaifuyuan, East District, Beijing 100730,China. yujch@csc.pumch.ac.cn

World J Gastroenterol. 1999 Apr;5(2):143-146.

AIM:To investigate the relationship between alanyl-glutamine (ALA-GLN) and glutathione (GSH) biosynthesis in hepatic protection.METHODS:Twenty male Wistar rats were randomly divided into two groups:one receiving standard parenteral nutrition (STD) and the other supplemented with or without ALA-GLN for 7 days. The blood and liver tissue samples were examined after 5-fluorouracil (5-FU) was injected peritoneally. RESULTS: The concentration measurements were significantly higher in ALA-GLN group than in STD group in serum GLN (687 < mol/L plus minus 50 < mol/L vs 505 < mol/L plus minus 39 < mol/L, P < 0.05), serum GSH (14 < mol/L plus minus 5 < mol/L vs 7 < mol/L plus minus 3 < mol/L, P <0.01) and in liver GSH content (6.9 < mol/g plus minus 2.5 < mol/g vs 4.4 < mol/g plus minus 1.6 < mol/g liver tissue, P <0.05). Rats in ALA-GLN group had lesser elevations in hepatic enzymes after 5-FU administration.CONCLUSION:The supplemented nutrition ALA-GLN can protect the liver function through increasing the glutathione biosynthesis and preserving the glutathione stores in hepatic tissue.

Chemoprevention trial of human hepatitis with selenium supplementation in China.

Yu SY, Li WG, Zhu YJ, Yu WP, Hou C Cancer Institute Chinese Academy of Medical Sciences, Beijing.

Biol Trace Elem Res 1989 Apr-May;20(1-2):15-22

A three-year study has been conducted for prevention of infectious hepatitis with supplementation of table salt fortified with 15 ppm anhydrous sodium selenite to the general population of 20,847 persons in a township M.Z. at Qidong County, Jiangsu Province, China. The results showed that the incidence of virus hepatitis infection in the test township was significantly lower than that of controls provided with normal table salt. The incidence rate of infectious hepatitis in the treated township M.Z. was 1.20 and 4.52 per 1,000, whereas the average incidence in the 6 surrounding control townships was 2.96 and 10.48 per 1,000 in 1986 and 1987, respectively. The incidence of hepatitis B surface antigen (HBsAg+) was 13.2% vs 19.23% for males and 10.42% vs 12.24% for females in the supplemented vs nonsupplemented neighboring township, respectively. Epidemiological studies have demonstrated that a low grain Se content is associated with a high regional incidence of hepatitis B virus infections.

Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong.

Yu SY, Zhu YJ, Li WG Cancer Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.

Biol Trace Elem Res 1997 Jan;56(1):117-24

High rates of hepatitis B virus (HBV) infection and primary liver cancer (PLC) are present in Qidong county. Epidemiological surveys demonstrated an inverse association between selenium (Se) level and regional cancer incidence, as well as HBV infection. Four-year animal studies showed that dietary supplement of Se reduced the HBV infection by 77.2% and liver precancerous lesion by 75.8% of ducks, caused by exposure to natural environmental etiologic factors. An intervention trial was undertaken among the general population of 130,471. Individuals in five townships were involved for observation of the preventive effect of Se. The 8-yr follow-up data showed reduced PLC incidence by 35.1% in selenized table salt supplemented vs the nonsupplemented population. On withdrawal of Se from the treated group, PLC incidence rate began to increase. However, the inhibitory response to HBV was sustained during the 3-yr cessation of treatment. The clinical study among 226 Hepatitis B Surface Antigen (HBsAg)-positive persons provided either 200 micrograms of Se in the form of selenized yeast tablet or an identical placebo of yeast tablet daily for 4 yr showed that 7 of 113 subjects were diagnosed as having PLC in the placebo group, whereas no incidence of PLC was found in 113 subjects supplemented with Se. Again on cessation of treatment, PLC developed at a rate comparable to that in the control group, demonstrating that a continuous intake of Se is essential to sustain the chemopreventive effect.

SUGGESTED READING

Hepatic glutathione content in patients with alcoholic and non alcoholic liver diseases.

Altomare E, Vendemiale G, Albano O. Istituto di Clinica Medica I, Universita' di Bari, Italy.

Life Sci 1988;43(12):991-8

Reduced and oxidized hepatic glutathione was evaluated during alcoholic and non alcoholic liver injury. We studied 35 chronic alcoholics, 20 patients with non alcoholic liver diseases, 15 control subjects. Hepatic glutathione was measured in liver biopsies and correlated with histology and laboratory tests. Alcoholic and non alcoholic patients exhibited a significant decrease of hepatic glutathione compared to control subjects (controls: 4.14 0.1 mumol/g liver; alcoholics: 2.55 0.1, p less than 0.001; non alcoholics 2.77 0.1, p less than 0.001). Oxidized glutathione was significantly higher in the two groups of patients compared to controls (controls: 4.4 0.2% of total; alcoholics 8.2 0.3, p less than 0.001; non alcoholics: 8.5 0.8, p less than 0.001). The decreased hepatic glutathione levels in patients with alcoholic and non alcoholic liver diseases may represent a contributing factor of liver injury and may enhance the risk of toxicity in these patients.

Thymosin alpha in the treatment of chronic hepatitis B: an uncontrolled open-label trial.

Amarapurkar D, Das HS. Bombay Hospital and Research Center, Mumbai.

Indian J Gastroenterol 2002 Mar-Apr;21(2):59-61

BACKGROUND: Interferon treatment for chronic hepatitis B has low efficacy and is associated with serious side effects. It is therefore important to assess the role of other drugs in the treatment of this condition. AIMS: To assess the efficacy and safety of thymosin alpha in 20 patients with hepatitis B-related liver disease. METHODS: Patients with chronic hepatitis B, HBV DNA positivity, ALT more than 1.5 times the upper limit of normal and liver biopsy showing chronic hepatitis or cirrhosis were treated with thymosin alpha 1.6 mg subcutaneously twice a week for 6 months. Biochemical and serological markers were assessed pre-treatment, immediately post treatment, and 6 months and 1 year after end of treatment. RESULTS: Of 20 patients, 15 had chronic hepatitis and 5 had cirrhosis on histology; 17 were HBeAg-positive and 3 were HBeAg-negative. Eight patients were interferon non-responders and 12 were naive patients. Four patients had end-of-treatment response and two additional patients had a delayed response within 6 months of treatment; one responder had a relapse within 1 year of treatment. Overall sustained response rate was 25% (5 of 20). No patient cleared HBsAg. Reduction in ALT levels was observed after treatment and persisted one year later. No significant side effects were observed. CONCLUSION: Thymosin alpha is a safe and effective alternative treatment modality in chronic hepatitis B.

Centrilobular endothelial cell injury by diquat in the selenium-deficient rat liver.

Atkinson JB, Hill KE, Burk RF. Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Lab Invest 2001 Feb;81(3):193-200

Low doses of diquat cause massive liver necrosis and death of selenium-deficient rats within a few hours. Protection against this injury by selenium correlates with the presence of selenoprotein P, an extracellular selenoprotein that associates with endothelial cells. Selenium-deficient rats were injected with diquat (10 mg/kg) and their livers were removed for light and electron microscopy at times up to 120 minutes after injection. Selenium-replete animals were studied before and 120 minutes after the same dose of diquat. With selenium deficiency, diquat caused injury to centrilobular endothelial cells. This injury was evident 20 minutes after diquat injection and progressed to cell loss at 60 minutes after diquat injection. At 120 minutes, endothelial cells were virtually absent from the centrilobular regions and hepatocytes in those areas were undergoing necrosis. Portal and midzonal areas remained normal in selenium-deficient livers, as did the entire liver lobule of selenium-replete rats. These findings indicate that the initial liver lesion in selenium-deficient rats given diquat is injury of the endothelial cells in the centrilobular region. After detachment of the endothelial cells, centrilobular hepatocytes undergo necrosis. We postulate that selenoprotein P protects the centrilobular endothelial cells against injury by oxidant molecules that result from diquat administration.

[Clinical study of 96 cases with chronic hepatitis B treated with jiedu yanggan gao by a double-blind method]. [Article in Chinese]

Chen Z Dept. of Hepatic Diseases, Beijing TCM Hospital.

Zhong Xi Yi Jie He Za Zhi 1990 Feb;10(2):71-4, 67

This paper reported 96 cases with chronic hepatitis B treated by a double-blind method. There were 51 cases of observation group(OG) and 45 cases of control group (CG). OG was treated with Jiedu Yanggan Gao consisting of Artemisia capillaris, Taraxacum mongolicum, Plantago seed, Cephalanoplos segetum, Hedyotis diffusa, Flos Chrysanthemi Indici, Smilax glabra, Astragalus membranaceus, Salviae miltiorrhizae, Fructus Polygonii Orientalis, Radix Paeoniae Alba, Polygonatum sibiricum, etc.). CG was prescribed with three charred medicinal herbs (charred Fructus Crataegi, charred Fructrus Hordei Germinatus, charred fermented mixture of several medical herbs and wheat bran). The average duration of treatment was five months. All 96 cases belong to the virus-duplication-type with positive HBsAg for over one year. Among them 65.5% of cases HBeAg, DNAP and HBV-DNA were positive. 20.8% of cases were positive in two out of the above tests. 13 data were compared statistically between two groups, and proved to be comparable (P greater than 0.05) before treatment. 27.3% and 66.7% of cases' ALT, AST returned to normal respectively in OG after treatment. However, in CG they were 9.1% and 22.2% (P less than 0.05). TTT returned to normal in 52% cases of OG and 44% in CG (P greater than 0.05). 20% cases HBeAg shifted to negative in OG, but 6.7% in CG. Cases with negative DNAP in OG occupied 34.2%, but 10.8% in CG. 31.6% cases' HBV-DNA changed to negative in OG, while 17.6% in CG. After comprehensive judgement, the total effective rate was 74.5% in OG and 24.4% in CG respectively (P less than 0.001). Eight cases were basically cured in OG and one case in CG. After one year's follow-up, one recurred in eight patients of OG, however the only one cured in CG still relapsed.

Efficacy of thymosin alpha1 in patients with chronic hepatitis B: a randomized, controlled trial.

Chien RN, Liaw YF, Chen TC, Yeh CT, Sheen IS. Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University, Taipei, Taiwan.

Hepatology 1998 May;27(5):1383-7

Thymosin alpha1 (Talpha) is an immune modifier that has been shown in a pilot study to be effective for chronic hepatitis B; this requires confirmation. Ninety-eight patients with clinicopathologically proven chronic hepatitis B were randomly allocated to 3 groups: 1) group A received a 26-week course of Talpha with a 1.6-mg subcutaneous injection two times a week (T6 group); 2) group B received the same regimen as group A, but Talpha therapy extended for 52 weeks (T12 group); and 3) group C served as a control group and was followed up for 18 months without specific treatment (T0 group). The three groups were comparable in clinicohistological features at entry. The complete virological response rate (clearance of serum hepatitis B virus [HBV] DNA and hepatitis B e antigen [HBeAg]) was higher in group A (40.6%) and group B (26.5%) than in group C (9.4%) (group A vs. group C: P=.004; group B vs. group C: P=.068) when assessed 18 months after entry, although complete response rates among these three groups were similar when first assessed at the end of therapy. There was a trend for complete virological response to increase or accumulate gradually after the end of Talpha therapy. None of the responders lost hepatitis B surface antigen. Blinded histological assessment showed a significant improvement in treated patients, particularly in lobular necroinflammation and scores excluding fibrosis. No significant side effects were observed. These results suggest that a 26-week course of Talpha therapy is effective and safe in patients with chronic hepatitis B.

Bioactivity of neolignans from fructus Schizandrae.

Li XY Shanghai Institute of Materia Medica, Chinese Academy of Sciences.

Mem Inst Oswaldo Cruz 1991;86 Suppl 2:31-7

Fructus Schizandrae sinensis Baill, a traditional Chinese medicine, used as tonic and sedative, has been shown at the beginning of 70's to lower the elevated serum glutamic-pyruvic transaminase (SGPT) levels of patients suffering from chronic viral hepatitis. During past 20 years, a series of neolignans have been isolated and identified as effective principles. Pharmacological studies revealed that they increased liver protein and glycogen synthesis, antagonized liver injuries from CCl4 and thioacetamide. The mechanism of SGPT lowering was considered as a hepato-protective and membrane stabilize action, although inhibition of the activity of liver GPT may also be existed. It was found that some principles of Schizandrae have an inducing effect on hepatic microsomal drug-metabolizing enzyme system P-450, thus explained their anti-toxic, anti-carcinogenic and anti-mutagenic effects. A synthetic derivative compound of Schisandrin called DDB has most of the above mentioned actions now used widely in China as a hepato-protective drug with high effectiveness in normalizing liver functions and very low side effects. From natural Schisandrin to synthesized DDB, pointed out a successful way in the development of new drugs from natural products.

Pharmacological properties of Dibenzo[a,c]cyclooctene derivatives isolated from Fructus Schizandrae Chinensis III. Inhibitory effects on carbon tetrachloride-induced lipid peroxidation, metabolism and covalent binding of carbon tetrachloride to lipids.

Liu KT, Lesca P

Chem Biol Interact 1982 Jul 15;41(1):39-47

Fructus Schizandrae, a traditional Chinese tonic, has been shown to lower the elevated serum glutamic pyruvic transaminase (SGPT) levels of patients with chronic viral hepatitis and several of its components decrease the hepatotoxicity of carbon tetrachloride (CCl4) in animals. This paper deals with the mechanism of protection against CCl4-hepatotoxicity of these compounds as well as of DDB, a synthetic analogue of Schizandrin (Sin) C. Of the seven components, Sin B and C, Schizandrol (Sol) B, Schizandrer (Ser) A and B, as well as dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxy-biphenyl-2,2'-dicarboxylate (DDB) were shown to inhibit CCl4-induced lipid peroxidation and [14C]Cl4 covalent binding to lipids of liver microsomes from phenobarbital(PB)-treated mice. The compounds also decreased carbon monoxide (CO) production and cofactor (NADPH, oxygen) utilization during CCl4 metabolization by liver microsomes. It may be postulated, therefore, that the hepatoprotective effect of certain components isolated from Fructus Schizandrae as well as DDB is due to their inhibitory effect on CCl4-induced lipid peroxidation and the binding of CCl4-metabolites to lipids of liver microsomes.

Glutamine and its relationship with intracellular redox status, oxidative stress and cell proliferation/death.

Mates JM, Perez-Gomez C, Nunez de Castro I, Asenjo M, Marquez J. Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Malaga, Campus de Teatinos, s/n 29071 Malaga, Spain. jmates@uma.es

Int J Biochem Cell Biol 2002 May;34(5):439-58

Glutamine is a multifaceted amino acid used for hepatic urea synthesis, renal ammoniagenesis, gluconeogenesis in both liver and kidney, and as a major respiratory fuel for many cells. Decreased glutamine concentrations are found during catabolic stress and are related to susceptibility to infections. Besides, glutamine is not only an important energy source in mitochondria, but is also a precursor of the brain neurotransmitter glutamate, which is likewise used for biosynthesis of the cellular antioxidant glutathione. Reactive oxygen species, such as superoxide anions and hydrogen peroxide, function as intracellular second messengers activating, among others, apoptosis, whereas glutamine is an apoptosis suppressor. In fact, it could contribute to block apoptosis induced by exogenous agents or by intracellular stimuli. In conclusion, this article shows evidences for the important role of glutamine in the regulation of the cellular redox balance, including brain oxidative metabolism, apoptosis and tumour cell proliferation.

Roles of selenium in endotoxin-induced lipid peroxidation in the rats liver and in nitric oxide production in J774A.1 cells.

Sakaguchi S, Iizuka Y, Furusawa S, Tanaka Y, Takayanagi M, Takayanagi Y. First Department of Hygienic Chemistry, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.

Toxicol Lett 2000 Dec 20;118(1-2):69-77

We examined the role of selenium (Se) in the mechanism of oxidative stress caused by endotoxin by feeding rats deficient a diet in this element. In rats fed the Se-deficient diet (concentration of Se, less than 0.027 microg g(-1)) for 10 weeks, Se level and glutathione peroxidase (GSH-Px) activity in the liver were about 47 and 43% lower, respectively, than those in rats fed a Se-adequate diet (Se, 0.2 microg g(-1)). Rat fed the Se-deficient diet and given endotoxin (6 mg kg(-1), i.p.) showed a mortality rates of about 43% at 18 h. Nevertheless, no lethality was observed with endotoxin (4 mg kg(-1), i.p.) challenge. Levels of serum lactate dehydrogenase and acid phosphatase leakage were significantly higher in Se-deficient rats than those in Se-adequate diet 18 h after endotoxin (4 mg kg(-1), i. p.) challenge. Superoxide anion generation and lipid peroxide formation in the liver of Se-deficient rat were markedly increased 18 h after endotoxin (4 mg kg(-1), i.p.) injection compared with those in the endotoxin/Se-adequate diet group, whereas non-protein sulfhydryl level in the liver after administration of endotoxin to Se-deficient rats was lower than that in Se-adequate rats treated with endotoxin. We investigated whether Se can suppress nitric oxide (NO) generation and cytotoxicity in endotoxin-treated J774A.1 cells. Treatment with Se (10(-6) M) markedly inhibited endotoxin (0.1 microg ml(-1))-induced NO production in J774A.1 cells. Se induced an increased activity of GSH-Px in cells after 24 h of incubation, suggesting that the preventive effect of Se on NO production in endotoxemia is due to the induction of Se-GSH-Px activity. However, Se did not affect endotoxin-induced cytotoxicity in J774A.1 cells. These findings suggested that the oxidative stress caused by endotoxin may be due, at least in part, to changes in Se regulation during endotoxemia.

Effects of kampo (Japanese herbal) medicine "sho-saiko-to" on DNA-synthesizing enzyme activity in 1,2-dimethylhydrazine-induced colonic carcinomas in rats.

Sakamoto S, Mori T, Sawaki K, Kawachi Y, Kuwa K, Kudo H, Suzuki S, Sugiura Y, Kasahara N, Nagasawa H Medical Research Institute, Tokyo Medical and Dental University, Japan.

Planta Med 1993 Apr;59(2):152-4

Sho-Saiko-To (SST) is a modified Japanese traditional Chinese herbal medicine containing seven medical plants: Bupleuri radix, Pinelliae tuber, Suxtallariae radix, Zizyphi fructus, Ginseng radix, Glycyrrhizae radix, and Zingiberis recens rhizoma. This preparation has been used in the treatment of some inflammatory diseases of the respiratory system and chronic hepatitis. In the present study, the effects of SST were investigated on the activities of DNA-synthesizing enzymes in 1,2-dimethylhydrazine (DMH)-induced colonic carcinomas in rats. Six-week administration of SST prevented nearly 100% of the body weight loss and the final number of the colonic carcinomas compared to those in the rats treated with DMH alone, and suppressed the enhanced activities of thymidylate synthetase (TS) and thymidine kinase (TK) which were involved in the de novo and salvage pathways of pyrimidine synthesis, respectively, in DMH-induced colonic carcinomas. These results indicate that SST may show directly and/or indirectly inhibitory effects on the development of colonic carcinomas.

Compromised hepatic detoxification in companion animals and its correction via nutritional supplementation and modified fasting.

Scanlan N. American Holistic Veterinary Medical Association, USA.

Altern Med Rev 2001 Sep;6 Suppl:S24-37

Dietary components play a crucial role in the health of companion animals, especially those exposed to elevated levels of toxins and free radicals. Investigation into animals' hepatic antioxidant and metabolite conjugation systems, and the metabolic processes that influence them, provides some understanding regarding the relationship of diet to disease prevention and treatment. A review of current literature and research publications suggests nutritional supplementation can be an effective treatment for animals suffering from increased oxidative stress and toxicity. The results of recent in vivo assessments, clinical trials, and observational studies show oral supplementation with vitamin E, selenium, glutathione, and taurine to be beneficial for both maintaining natural antioxidant systems and protecting against a number of degenerative diseases associated with free radical damage and toxin exposure. In many instances, it has been observed that the introduction of specific nutrients positively influences the health status, symptomatic presentation, and life span of animals whose natural detoxification systems are compromised.

Reduced glutathione concentration in erythrocytes of patients with acute and chronic viral hepatitis.

Swietek K, Juszczyk J. Department of Infectious Diseases, Karol Marcinkowski University of Medical Sciences, Poznan, Poland.

J Viral Hepat 1997 Mar;4(2):139-41

Reduced glutathione (GSH), the main intracellular mechanism that protects against oxidative stress, is the subject of considerable interest in viral hepatitis. In patients with chronic hepatitis C, results reported from different centres are controversial, demonstrating either a reduction or an elevation of GSH concentration. The aim of this study was to evaluate the glutathione concentration in erythrocytes (normal range 2.45 0.15 mmol l-1) in patients with acute and chronic viral hepatitis. In 52 patients with acute viral hepatitis (hepatitis A virus (HAV), hepatitis B virus (HBV) and hepatitis C virus (HCV) infection) there was marked reduction of GSH at the beginning of the disease (0.79 0.43 mmol l-1, P < 0.001) with high alanine aminotransferase (ALT) activity (1549 772.9 IU l-1). In 37 patients with chronic HCV infection the mean value of GSH was below the normal range (1.92 0.62 mmol l-1, P < 0.001). In 60% of patients (n = 22), depletion of GSH was observed and 40% (n = 15) presented with a normal concentration of GSH. In 10 patients with chronic HBV infection the mean value of GSH was also below the normal range (1.93 0.32 mmol l-1, P < 0.001); in 80% of cases (n = 8) depletion of GSH was observed and 20% of patients (n = 2) had normal GSH concentrations. The ALT activity was not significantly different in patients with depleted and normal GSH concentrations (P > 0.05) in groups with chronic HBV and HCV infection.

The effects of chronic hepatitis C and B virus infections on liver reduced and oxidized glutathione concentrations.

Tanyalcin T, Taskiran D, Topalak O, Batur Y, Kutay F. Department of Biochemistry, Ege University School of Medicine, Bornova 35100, Izmir, Turkey

Hepatol Res 2000 Aug;18(2):104-109

The aim of this study was to evaluate the effects of hepatitis B and C virus infections on liver glutathione status. Reduced and oxidized glutathione levels were determined in liver biopsy specimens obtained from patients with chronic liver disease including chronic active hepatitis and cirrhosis. In patients with hepatitis B virus infections, GSH and GSH/GSSG levels were significantly low compared with those in controls (P<0.01). There was a significant negative correlation between histological activity indices (HAI) and hepatic GSSG levels only in patients with chronic HCV infection (P<0.01; r=-0.895). In addition to this, we also found a positive correlation between indices (HAI) and GSH/GSSG of the same group (r=0.915; P<0.05). These observations suggest that HBV and HCV infections have different effects on liver glutathione status based on diverse mechanisms.

Evidence of hepatic endogenous hydrogen peroxide in bile of selenium-deficient rats.

Ueda Y, Matsumoto K, Endo K. Department of Physical Chemistry, Showa Pharmaceutical University, 3-3165, Higashi-Tamagawagakuen, Machida, Tokyo, 194-8543, Japan.

Biochem Biophys Res Commun 2000 May 19;271(3):699-702

Hepatic endogenous hydrogen peroxide (H(2)O(2)) in bile of selenium-deficient rats (SeD) was for the first time found using the electron spin resonance (ESR) spin-trap technique, and the relationship between glutathione peroxidase (GPX) activity and H(2)O(2) amount is discussed. Normal rats and four groups of rats fed a selenium-deficient diet with different feeding periods were examined. The results showed that the GPX activity decreased depending on the feeding period with the selenium-deficient diet and that the hepatic endogenous H(2)O(2) amount in the bile of the rats fed the selenium-deficient diet for the longest period (a week before birth to 8 weeks old) was drastically higher than those in other groups of rats (P < 0.005). We found that generation of H(2)O(2) due to the decrease in the GPX activity has a threshold value. The results suggest that an exposure to selenium deficiency for long term will cause oxidative stress. Copyright 2000 Academic Press.

Glutathione S-transferase expression in hepatitis B virus-associated human hepatocellular carcinogenesis.

Zhou T, Evans AA, London WT, Xia X, Zou H, Shen F, Clapper ML. Division of Population Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.

Cancer Res 1997 Jul 1;57(13):2749-53

Hepatitis B virus (HBV) and aflatoxin B1 represent the main risk factors for the development of hepatocellular carcinoma (HCC) in areas endemic for liver cancer. The glutathione S-transferases (GSTs) are a family of Phase II detoxification enzymes that catalyze the conjugation of a wide variety of endogenous and exogenous toxins, including aflatoxin B1, with glutathione. This study characterizes the GST isoenzyme composition (alpha, mu, and pi) of both HBV-infected normal hepatic tissues and HCCs. Analysis of matched pairs of hepatic tissue (normal and tumor) from 32 HCC patients indicated that total GST activity was significantly higher in normal tissues than in tumor tissues, although the percentage of samples expressing GST alpha and pi was equivalent. GST mu was detected by Western blot in the normal tissue from 87.5% of the subjects possessing the GST M1 gene but only 28.6% of the corresponding tumor tissues. The GST activity of normal tissue from GST M1 null patients was significantly decreased as compared to that of subjects possessing the GST M1 gene (264.6 and 422.2 nmol/min/mg, respectively; P = 0.005). GST pi appeared to be overexpressed in the normal tissue of GST M1 null patients, a potential compensatory effect. Patients positive for HBV DNA had significantly lower GST activity than those who were HBV negative (302.1 versus 450.0 nmol/min/mg, respectively; P = 0.02). These results suggest that cellular protection within the human liver is compromised by HBV infection and further decreased during hepatocellular tumorigenesis.