Toxicity of hepatotoxins: new insights into mechanisms and therapy

Bibliography

• BERRY MN, HALLS HJ, GRIVELL MB: Techniques Q!for pharmacological and toxicological studies with iso-lated hepatocyte suspensions. Life Sci. (1992) 21:1–16.
   Google Scholar
• WU J, DANIELSSON A, LINDSTROM P, KARLSSON K, SEH-LIN J: The protective effects of calcium channel block-ers on bromobenzene-induced damage to isolated rat hepatocytes. Inhibition of phenylephrine stimulated calcium oscillations. Scand. j Gastroenterol. (1995) 30:590–600.
   PubMed Web of Science ®Google Scholar
• WU J, SODERBERGH H, KARLSSON K, DANIELSSON A: Protective effect of S-adenosyl-L-methionine on bro-mobenzene- or D-galactosamine toxicity to isolated rat hepatocytes. Hepatology (1996) 23:359–365.
   PubMed Web of Science ®Google Scholar
• NELSON SD: Molecular mechanisms of the hepatotox-icity caused by acetaminophen. Sem. Liver Dis. (1990) 10:267–278.
   PubMed Web of Science ®Google Scholar
• ARNON R, DEGLI ESPOSTI S, ZERN MA: Molecular bio-logical aspects of alcohol-induced liver disease. Alcohol Clin. Exp. Res. (1995) 19:247–256.
   PubMed Web of Science ®Google Scholar
• LIEBER CS: Ethanol metabolism, cirrhosis and alcohol-ism. Clin. Chim. Acta (1997) 257:59–84.
   PubMed Web of Science ®Google Scholar
• •This review delineates metabolic pathways of ethanol and their relationship with chronic alcohol liver disease and al-coholism, as well as therapeutic approaches.
   Google Scholar
• PUMFORD NR, HALMES NC, HINSON JA: Covalent binding of xenobiotics to specific proteins in the liver. Drug Met. Rev. (1997) 29:39–57.
   PubMed Web of Science ®Google Scholar
• •The review provides a large body of the evidence for cova-lent binding of intermediate metabolites of xenobiotics to proteins, which is considered as a primary mechanism for hepatotoxicity.
   Google Scholar
• GILBSON JD, PUMFORD NR, SAMOKYSZYN VM, HINSON JA: Mechanism of acetaminophen-induced hepatotox-icity: covalent binding versus oxidative stress. Chem. Res. Toxicol. (1996) 9:580–585.
   PubMed Web of Science ®Google Scholar
• LIEBER CS: Cytochrome P-4502E1: its physiological and pathological role. Physiol Rev. (1997) 77:517–544.
   PubMed Web of Science ®Google Scholar
• •The review summarised the roles of cytochrome P-450 and their subtypes in biotransformation and drug metabolism, and compared the effects of inhibitors for cytochrome P-450 subtypes in xenobiotic-associated liver injury.
   Google Scholar
• LI Y, WANG EJ, CHEN L, STEIN AP, REUHL KR, YANG CS: Effects of phenethyl isothiocyanate on acetamino-phen metabolism and hepatotoxicity in mice. Toxicol. Appl. Pharmacol. (1997) 144:306–314.
   PubMed Web of Science ®Google Scholar
• WU J, NORTON PA: Animal models of liver fibrosis. Scand.J. Gastroenterol. (1996) 3:1137–1143.
   Google Scholar
• BOUR ES, WARD LK, CORNMAN GA, ISOM HC: Tumor ne-crosis factor-a-induced apoptosis in hepatocytes in long-term culture. Am. J. Pathol. (1996) 148:485–495.
   PubMed Web of Science ®Google Scholar
• GRESSNER AM, POLZER B, LAHME B, MANNHERZ HG: In-duction of rat liver parenchymal cell apoptosis byhepatic myofibroblasts via transforming growth fac-tor beta. Hepatology (1996) 23:571–581.
   PubMed Web of Science ®Google Scholar
• SANCHEZ A, ALVAREZ AM, BENITO M, FABREGAT I: Cycloheximide prevents apoptosis, reactive oxygen species production, and glutathione depletion in-duced by transforming growth factor-n in fetal rat he-patocytes in primary culture. Hepatology (1997) 26:935–943.
   PubMed Web of Science ®Google Scholar
• SIMPSON KJ, LUKACS NW, COLLETTI L, STRIETER RM,KUNKEL SL: Cytokines and the liver. J. Hepatol. (1997) 27:1120–1132.
   PubMed Web of Science ®Google Scholar
• •This is a comprehensive review of physiological or patho-physiological roles of a variety of cyokines in liver diseases, as well as their potential therapeutic applications.
   Google Scholar
• WU J, KUNCIO GS, ZERN MA: Human liver growth in fi-brosis and cirrhosis. In: Liver Growth and Repair: from Basic Science to Clinical Practice. Strain AJ, Deihl AM, (Eds.), Chapman & Hall (Thomson Science Publishing), London, UK (1998):558–576.
   Google Scholar
• KUROSE I, HIGUCHI H, MIURA S et al.: Oxidative stress-mediated apoptosis of hepatocytes exposed to acute ethanol intoxication. Hepatology (1997) 25:368–378.
   PubMed Web of Science ®Google Scholar
• DE LEVE LD, KAPLOWITZ N: Mechanisms of drug-induced liver disease. Gastroenterol. Clin. N Am. (1995) 24:787–810.
   PubMed Web of Science ®Google Scholar
• MEHENDALE HM, ROTH RA, JAY GANDOLFI A et al.: Novel mechanisms in chemically induced hepatotox-icity. FASEB J (1994) 8:1285–1295.
   Google Scholar
• HOLT C, CSETE M, MARTIN P: Hepatotoxicity of anes-thetics and other central nervous system drugs. Castro-enterol. Clin. N Am. (1995) 24:853–874.
   PubMed Web of Science ®Google Scholar
• VAN PELT FNAM, STRAUB P, MANNS MP: Molecular basis of drug-induced immunological liver injury. Sem. Liver Dis. (1995) 15:283–300.
   PubMed Web of Science ®Google Scholar
• TAMAYO RP: Is cirrhosis of the liver experimentally produced by CC14 and adequate model of human cir-rhosis? Hepatology (1983) 3:112–120.
   PubMed Web of Science ®Google Scholar
• FAROON 0, DEROSA CT, SMITH L et al.: ATSDR evalua-tion of health effects of chemicals. 1. Carbon tetrachloride-health effects, toxicokinetics, human exposure and environmental fate. Tox. Indust. Health (1994) 10:1s–123s.
   Google Scholar
• POLI G: Liver damage due to free radicals. Br. Med. Bull. (1993) 49:604–620.
   PubMed Web of Science ®Google Scholar
• STOYANOVSKY DA, CESERBAUM AL: Thiol oxidation and cytochrome P450-dependent metabolism of CC14 triggers Ca2+ release from liver microsomes. Biochem-istry (1996) 35:15839–15845.
   PubMed Web of Science ®Google Scholar
• IP SP, POON MK, CHE CT, NG KH, KONG YC, KO KM: Schisandrin B protects against carbon tetrachloride toxicity by enhancing the mitochondrial glutathione redox status in mouse liver. Free Rad. Biol. Med. (1996) 21 :709–712.
   PubMed Web of Science ®Google Scholar
• CONNOR HD, LACAGNIN LB, KNECHT KT, THURMAN RG,MASON RP: Reaction of glutathione with a free radical metabolite of carbon tetrachloride. Mol. Pharmacol (1990) 37:443–451.
   PubMed Web of Science ®Google Scholar
• LIU SL, DEGLI ESPOSTI S, YAO T, DIEHL AM, ZERN MA: Vi-tamin E therapy of acute CC14-induced hepatic injury in mice is associated with inhibition of nuclear factor Kappa B binding. Hepatology (1995) 22:1474–1481.
   PubMed Web of Science ®Google Scholar
• JONES BE, CZAJA MJ: Mechanisms of hepatic toxicity III. Intracellular signaling in response to toxic liver in-jury. Am. J. Physic)]. (1998) 275:G874–G878.
   Google Scholar
• ••This leading article discusses the effects of toxic injury on ac-tivation of receptor-coupled signal transduction and their known functions in regulating hepatocyte death and prolif-eration following injury.
   Google Scholar
• JIANG Z, YOU DY, CHEN XC, WU J: Monitoring of serum markers of fibrosis during CC14-induced liver damage. Effects of anti-fibrotic agents. J. Hepatol. (1992) 16:282–289.
   Google Scholar
• ZHU JL, FRIZELL E, LIU SL, WU J, MIRZA AA, ZERN MA: In-hibitory effect of rapamycin on CC14-induced hepatic fibrosis in rats. Hepatology (1997) 24:166A.
   Google Scholar
• WU J, LINDSTROM P, DANIELSSON A, SEHLIN J: Insulin secretion in pancreatic islets from rats with cirrhosis. Hepatol. (1994) 21:332–339.
   Web of Science ®Google Scholar
• MACKINNON M, CLAYTON C, PLUMMER J et al.: Iron overload facilitates hepatic fibrosis in the rat alco-hol/low-dose carbon tetrachloride model. Hepatology (1995) 21:1083–1088.
   PubMed Web of Science ®Google Scholar
• OZEKI T, FUNAKOSHI K, IWAKI K: Rapid induction of cirrhosis by administration of carbon tetrachloride plus phospholipase D. Br. J. Exp. Path. (1985) 66:385–390.
   PubMed Web of Science ®Google Scholar
• BOSMA A, BROUWER A, SEIFERT WF, KNOOK DL: Syner-gism between ethanol and carbon tetrachloride in the generation of liver fibrosis. J. Pathol. (1988) 156:15–21.
   PubMed Web of Science ®Google Scholar
• CHIARPOTTO E, BIASI F, COMOGLIO A, LEONARDUZZIG, POLI G, DIANZANI MU: CC14-induced of hepatocytes free arachidonate level: pathogenesis and contribu-tion to cell death. Chem. Biol. Interaction (1990) 74:195–206.
   PubMed Web of Science ®Google Scholar
• POLI G, DIANZANI MU, CHEESEMAN KH, SLATER TF, LANG J, ESTERBAUER H: Separation and characteriza-tion of the aldehydic production of lipid peroxidation stimulated by carbon tetrachloride or ADP-iron in iso-lated rat hepatocytes and rat liver microsomal suspen-sions. Biochem. J. (1985) 227:629–638.
   PubMed Web of Science ®Google Scholar
• THURMAN RG: Mechanisms of hepatic toxicity II. Alco-holic liver injury involves activation of Kupffer cells by endotoxin. Am. J. Physic)]. (1998) 275:G605–G611.
   Google Scholar
• PINZANI M: Hepatic stellate (Ito) cells: expanding roles for a liver-specific pericyte. j Hepatol. (1995) 22:700–706.
   PubMed Web of Science ®Google Scholar
• NIEMELA 0, PARKKILA S, YLA-HERTTUALA S, VIL-LANUEVA J, RUEBNER B, HALSTED CH: Sequential acetal-dehyde production, lipid peroxidation and fibrogenesis in micropig model of alcohol-induced liver disease. Hepatology (1995) 22:1208–1214.
   PubMed Web of Science ®Google Scholar
• CLOT P, ALBANO E, ELIASSON E et al.: Cytochrome P4502E1 hydroxyethyl radical adducts as the major antigen in autoantibody formation among alcoholics. Gastroenterology (1996) 111:206–216.
   PubMed Web of Science ®Google Scholar
• ALBOANO E, TOMASI A, GORIA-GATTI L et al: Role ofethanol-inducible cytochrome P450 (P450IIE1) in catalysing the free radical activation of aliphatic alco-hol. Biochem. Pharmacol. (1991) 41:1895–1902.
   PubMedGoogle Scholar
• REINKE LA, MOORE DR, MCCAY PB: Free radical forma-tion in livers of rats treated acutely and chronically with alcohol. Alcoholism an. Exp. Res. (1997) 21:642–646.
   PubMed Web of Science ®Google Scholar
• •This study demonstrated that chronic alcohol administration causes development of oxidative conditions in the liver, which subsequently lead to ROS generation.
   Google Scholar
• HIGUCHI H, KUROSE I, KATO S, MIURA S, ISHII H:Ethanol-induced apoptosis and oxidative stress in he-patocytes. Alcoholism Clin. Exp. Res. (1996) 20:340A–346A.
   Google Scholar
• PAROLA M, PINZANI M, CASINI A et al.: Stimulation oflipid peroxidation or 4-hydroxynonenal treatment in-creases procollagen al (0 gene expression in human fat-storing cells. Biochem. Biophys. Res. Commun. (1993) 194:1044–1050.
   PubMed Web of Science ®Google Scholar
• JOHNSTON SC, PELLETIER LL: Enhanced hepatotoxicityof acetaminophen in the alcoholic patient. Two case reports and a review of the literature. Medicine (1997) 76:185–191.
   Google Scholar
• LAMB RG, KOCK JC, SNYDER JW, HUBAND SM, BUSH S:An in vitro model of ethanol-dependent liver cell in-jury. Hepatology (1994) 19:174–182.
   PubMed Web of Science ®Google Scholar
• GLASCOTT PA, GILFOR E, SERRONI A, FARBER JL: Inde-pendent antioxidant action of vitamins E and C in cul-tured rat hepatocytes intoxicated with allyl alcohol. Biochem. Pharmacol. (1996) 52:1245–1212.
   PubMed Web of Science ®Google Scholar
• BAILEY SM, CUNNINGHAM CC: Acute and chronic etha-nol increases reactive oxygen species generation and decreases viability in fresh isolated rat hepatocytes. Hepatology (1998) 28:1318–1326.
   PubMed Web of Science ®Google Scholar
• •Findings of this paper suggest that acute and chronic etha-nol exposure exacerbates mitochondrial ROS production, contributing to hepatocellular death.
   Google Scholar
• LIEBER CS, ROBINS SJ, LI JJ et al.: Phosphatidylcholine protects against fibrosis and cirrhosis in the baboon. Gastroenterology (1994) 106:152–159.
   PubMed Web of Science ®Google Scholar
• FONTANA RJ, WATKINS PB: Genetic predisposition to drug-induced liver disease. Gastroenterol. Clin. N Am. (1995) 24:811–838.
   PubMed Web of Science ®Google Scholar
• MAKIN AJ, WENDON J, WILLIAMS R: A 7-year experienceof severe acetaminophen-induced hepatotoxicity (1987-1993). Gastroenterology (1995) 109: 1907-1916.
   Google Scholar
• MANAUTOU JE, TVEIT A, HOIVIK DJ, KHAIRALLAH EA,COHEN SD: Protection by clofibrate against acetamino-phen hepatotoxicity in male CD-1 mice is associated with an early increase in biliary concentration of acetaminophen-glutathione adducts. Toxicol. Appl. Pharmacol. (1996) 140:30–38.
   PubMed Web of Science ®Google Scholar
• SHEN W, KAMENDULIS LM, RAY SD, CORCORAN GB: Acetaminophen-induced cytotoxicity in cultured mouse-hepatocytes: correlation of nuclear Ca2+ accu-mulation and early DNA fragmentation with cell death. Toxicol. Appl. Pharmacol. (1991) 111:242–254.
   PubMed Web of Science ®Google Scholar
• NICOTERA P, BELLOMO G, ORRENIUS S: Calcium-mediated mechanisms in chemically induced cell death. Ann. Rev. Pharmacol. Toxicol. (1992) 32:449–470.
   PubMed Web of Science ®Google Scholar
• ELLOUK-ACHARD S, MAWET E, THIBAULT N, DUTERTRE-CATELLA H, THEVENIN M: Protective effect of nifedipine against cytotoxicity and intracellular cal-cium alterations induced by acetaminophen in rat he-patocyte cultures. Drug Chem. Toxicol. (1995) 18:105–117.
   PubMed Web of Science ®Google Scholar
• SHEN W, KAMENDULIS LM, RAY SD, CORCORAN GB: Acetaminophen-induced cytotoxicity in cultured mouse hepatocytes: effects of Ca2±-endonuclease, DNA repair, and glutathione depletion inhibitors on DNA fragmentation and cell death. Toxicol. App. Pharmacol. (1992) 112:32–40.
   PubMed Web of Science ®Google Scholar
• MINAMIDE Y, HORIE T, TOMARU A, AWAZU S: Spontane-ous chemiluminescence production, lipid peroxida-tion, and covalent binding in rat hepatocytes exposed to acetaminophen. J. Pharmaceut. ScL (1998) 87:640–646.
   PubMed Web of Science ®Google Scholar
• ••It was demonstrated in this paper that lipid peroxidationcontributes to the APAP-induced hepatotoxicity in the early stage of the toxic process.
   Google Scholar
• VALE JA, PROUDFOOT AT: Paracetamol (acetamino-phen) poisoning. Lancet (1995) 346:547–552.
   PubMed Web of Science ®Google Scholar
• PUTNEY JW: Calcium signaling: up, down, up, down what's the point? Science (1998) 279:191–192.
   PubMed Web of Science ®Google Scholar
• •The paper discusses two fundamental questions about cal-cium oscillations: How do these oscillations arise? What is their function?
   Google Scholar
• KONINCK PD, SCHULMAN H: Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations. Science (1998) 279:227–230.
   PubMed Web of Science ®Google Scholar
• •The authors demonstrated the relationship between fre-quency of calcium oscillations and calmodulin-dependent protein kinase II (CaM kinase II).
   Google Scholar
• MONKS TJ, LAU SS: Reactive intermediates and their toxicological significance. Toxicology (1988) 52:1–53.
   PubMed Web of Science ®Google Scholar
• WU J, KARLSSON K, DANIELSSON A: Effects of vitamin E, ascorbic acid and catalase on bromobenzene- and hy-drogen peroxide-induced intracellular oxidation and single strand DNA breakage in Hep G2 cells. J. Hepatol. (1997) 26:669–677.
   PubMed Web of Science ®Google Scholar
• WANG BH, ZUZEL KA, BILLINGTON D: Protective effectsof aged garlic extract against bromobenzene toxicity to precision cut rat liver slices. Toxicology (1998) 126:213–222.
   PubMed Web of Science ®Google Scholar
• RYHÄNEN L, ALA-KOKKO L, SAVOLAINEN ER: The effectof malotilate on Type III and Type IV collagen, laminin and fibronectin metabolism in dimethylnitrosamine-induced liver fibrosis in the rat. J. Hepatol. (1996) 24:238–245.
   PubMed Web of Science ®Google Scholar
• SHIKATA N, OYAIZU T, SENZAKI H, UEMURA Y, TSUB-URA A: Liver apoptosis after dimethylnitrosamine ad-ministration in shrews. Exp. Toxicol. Pathol. (1996) 48:307–311.
   PubMed Web of Science ®Google Scholar
• KAMENDULIS LM, CORCORAN GB: Dimethylnitro-samine -induced DNA damage and toxic cell death in cultured mouse hepatocytes. J. Toxicol. Environ. Health (1995) 46:31–46.
   PubMed Web of Science ®Google Scholar
• WITZMANN FA, FULTZ CD, MANGIPUDY RS, MEHEN-DALE HM: Two-dimensional electrophorectic analysis of compartment-specific hepatic protein charge modi-fication induced by thioacetamide exposure in rats. Fund. Appl. Toxicol. (1996) 31:124–132.
   PubMedGoogle Scholar
• CLAWSON GA, BENEDICT CM, KELLEY MR, WEISZ J: Focalnuclear hepatocyte response to oxidative damage fol-lowing low dose thioacetamide intoxication. Carcino-genesis (1997) 18:1663–1668.
   PubMed Web of Science ®Google Scholar
• MORI T, OKANOUE T, SAWA Y, HORI N, OHTA M, KA-GAWA K: Defenestration of the sinusoidal endothelial cell in a rat model of cirrhosis. Hepatology (1993) 17:891–897.
   PubMed Web of Science ®Google Scholar
• DIEZ-FERNANDEZ C, SANZ N, BOSCA L, HORTELANO S,CASCALES M: Involvement of nitric oxide synthesis in hepatic perturbations induced in rats by a necrogenic dose of thioacetamide. Br. J. Pharmacol. (1997) 121:820–826.
   PubMed Web of Science ®Google Scholar
• DECKER K: Mechanisms and mediators in hepatic ne-crosis. Jpn. Gastroenterol. (1993) 28:20s–25s.
   Google Scholar
• OMAR H EL-D, SANDERS RA, WATKINS JB: Minimal effectof acute experimental hepatitis induced by lipopoly-saccharide/d-galactosamine on biotransformation in rats. Biochem. Pharmacol. (1996) 52:1921–1924.
   PubMed Web of Science ®Google Scholar
• SANTUCCI L, FIOROCCI S, CHIOREAN M et al.: Inter-leukin 10 reduces lethality and hepatic injury induced by lipopolysaccharide in galactosamine-sensitized mice. Gastroenterology (1996) 111:736–744.
   PubMed Web of Science ®Google Scholar
• KOMATSU Y, SHIRATORI Y, KAWASE T et al.: Role ofpolymorphonuclear leukocytes in galactosamine hepatitis: mechanism of adherence to hepatic endo-thelial cells. Hepatology (1994) 20:1548–1556.
   PubMed Web of Science ®Google Scholar
• HESPELING U, PUSCHEL GP, JUNGERMANN K, GOTZE 0,ZWIRNER J: Stimulation of glycogen phosphorylase in rat hepatocytes via prostanoid release from Kupffer cells by recombinant rat anaphylatoxin C5a but not by native human C5a in hepatocyte/Kupffer cell co-cultures. FEBS Lett. (1995) 372:108–112.
   PubMed Web of Science ®Google Scholar
• STEINHORN DM, CERRA FB: Comparative effects of lipo-polysaccharide on newborn versus adult rat hepato-cyte and nonparenchymal cell cocultures. Grit. Care Med. (1997) 25:121–127.
   PubMed Web of Science ®Google Scholar
• MCMILLAN JM, JOLLOW DJ: Macrophage enhancementof galactosamine hepatotoxicity using a rat hepatocyte culture system. Res. Commun. Mol. Pathol. Pharmacol (1995) 88:327–338.
   PubMed Web of Science ®Google Scholar
• JONKER AM, DIJKHUS FWJ, HARDONK MJ, MOERKERK P,KATE JT, GROND J: Immunohistochemical study of he-patic fibrosis induced in rats by multiple galacto-samine injections. Hepatology (1994) 19:775–781.
   PubMed Web of Science ®Google Scholar
• MAUGER JP, CLARET M: Calcium channels in hepato-cytes. j Hepatol (1988) 7:278–282.
   PubMed Web of Science ®Google Scholar
• TSUNODA Y: Oscillatory Ca2+ signalling and its cellular function. New Biol. (1991) 3:3–17.
   PubMedGoogle Scholar
• YAMAMOTO HA: Relation of Ca2+ accumulation and lipid peroxidation with CC14-induced toxicity in the rat liver. Pharmacol Toxicol. (1990) 66:213–216.
   PubMedGoogle Scholar
• MURATA M, NORDEN M, UMESHITA K eta].: Role of infra-cellular calcium in superoxide-induced hepatocyte in-jury. Hepatology (1994) 19:1223–1228.
   Google Scholar
• FARBER JL: Mechanisms of cell injury by activated oxy-gen species. Environ. Health Persp. (1994) 102:S17–S24.
   Google Scholar
• MCCONKEY DJ, ORRENIUS S: The role of calcium in the regulation of apoptosis. Biochem. Biophys. Res. Com-mun. (1997) 239:357–366.
   PubMed Web of Science ®Google Scholar
• ••This review summarises the role of Ca2+ in apoptosis withinthe context of what is known about the core components of the effector machinery for apoptosis.
   Google Scholar
• LEMASTERS JJ, BOND JM, CURRIN RT et al.: Reperfusion injury to heart and liver cells, protection by acidosis during ischemia and a 'pH paradox' after repercus-sion. In: Surviving hypoxia: mechanisms of control and ad-aptation. Hochachka PW, Lutz PL, Sich T, Rosenthal M, van den Thillart G, (Eds.), CRC Press, Boca Raton, Florida, USA (1993)495–507.
   Google Scholar
• HARMAN AW, MAHER SO, BRUCHAM PC, MADSEN BW: Mol. Pharmacol. (1992) 41:665–670.
   Google Scholar
• SAHU SC, GRAY GC: Lipid peroxidation and DNA dam-age induced by morin and naringenin in isolated rat liver nuclei. Food Chem. Toxicol (1997) 35:443–447.
   PubMed Web of Science ®Google Scholar
• KRISTAL B, PARK BK, YU BP: 4-Hydroxyhexenal is a po-tent inducer of the mitochondrial permeability transi-tion. J. Biol. Chem. (1996) 271:6033–6038.
   PubMed Web of Science ®Google Scholar
• LEMASTERS JJ, THURMAN RG: Hypoxia and reperfusion injury to liver. Prog Liver Dis. (1993) 11:85–114.
   PubMedGoogle Scholar
• YAO T, ESPOSTI SD, HUANG L, ARNON R, SPANGEN-BERGER A, ZERN MA: Inhibition of carbon tetrachloride-induced liver injury by liposomes con-taining vitamin E. Am. J. Physiol. (1994) 267:G476–G484.
   PubMed Web of Science ®Google Scholar
• WU J, KARLSSON K, DANIELSSON A: Protective effect of Trolox C, vitamin C and catalase on bromobenzene-induced damage to rat hepatocytes. Scand. J. Gastroen-terol. (1996) 31:797–803
   PubMed Web of Science ®Google Scholar
• GANEY PE, BAILIE MB, VANCISE S et al.: Activated neu-trophils from rat injured isolated hepatocytes. Lab. In-vest. (1994) 70:53–60.
   Google Scholar
• CASINI A, CENT E, SALZANO R et al: Neutrophil-derived superoxide anion induces lipid peroxidation and stimulates collagen synthesis in human hepatic stel-late cells: role of nitric oxide. Hepatology (1997) 25:361–367.
   PubMed Web of Science ®Google Scholar
• HALLIWELL B, GUTTERIDGE JMC: Lipid peroxidation: aradical chain reaction. In: Free Radicals in Biology and Medicine, 2nd edition. Halliwell B, Gutteridge JMC, (Eds.), Clarendon Press, Oxford, UK (1989):188–266.
   Google Scholar
• SUSA N, UENO S, FURUKAWA Y, SUGIYAMA M: Protec-tive effect of desferoxamine on chromium (VD-i-nduced DNA single-strand breaks, cytotoxicity, and lipid peroxidation in primary cultures of rat hepato-cytes. Arch. Toxicol. (1997) 71:345–350.
   PubMed Web of Science ®Google Scholar
• MARKLUND SL: Superoxide dismutase, free oxygenradicals and inflammation. Adv. Clin. Enzymol. (1986) 4:135–144.
   Google Scholar
• MARKLUND SL: Extracellular-superoxide dismutase inhuman tissues and human cell lines. J. Clin. Invest. (1984) 74:1398–1403.
   PubMed Web of Science ®Google Scholar
• HAMPTON MB, ORRENIUS S: Dual regulation of caspaseactivity by hydrogen peroxide - implications for apop-tosis. FEBS Letts (1997) 414:552–556.
   PubMed Web of Science ®Google Scholar
• LEIST M, GANTNER F, NAUMANN H et al.: Tumor necro-sis factor-induced apoptosis during the poisoning of mice with hepatotoxins. Gastroenterology (1997) 112:923–934.
   PubMed Web of Science ®Google Scholar
• •The study indicates that hepatotoxins may induce liver fail-ure by an indirect mechanism involving sensitisation of pa-renchymal cells towards endogenously produced TNF-a.
   Google Scholar
• KITADE H, SAKITANI K, INOUE K eta].: Interleukin-lb markedly stimulates nitric oxide formation in the ab-sence of other cytokines or lipopolysaccharide in pri-mary cultured rat hepatocytes but not in Kupffer cells. Hepatology (1996) 23:797–802.
   Google Scholar
• DE VERA ME, GELLER DA, BILLIAR TR: Hepatic inducible nitric oxide synthase: regulation and function. Bio-chem. Soc. Transact. (1995) 23:1008–1013.
   PubMed Web of Science ®Google Scholar
• SERGENT 0, GRIFFON B, MOREL I et al.: Effect of nitric oxide on iron-mediated oxidative stress in primary rat hepatocyte culture. Hepatology (1997) 25:122–127.
   Google Scholar
• •Findings in the study suggest that nitric oxide acts as an anti-oxidant in iron-mediated oxidative stress in rat hepatocytes.
   Google Scholar
• KUROSE I, HIGUCHI H, YONEI Y: Rat Kupffer cell-derived nitric oxide suppresses proliferation and in-duces apoptosis of syngeneic hepatoma cells. Gastro-enterology (1996) 111:1058–1070.
   PubMed Web of Science ®Google Scholar
• KUROSE I, MIURA S, HIGUCHI H eta].: Increased nitric oxide synthase activity as a cause of mitochondrial dysfunction in rat hepatocytes: roles for tumor necro-sis factor-a. Hepatology (1996) 24:1185–1192.
   Google Scholar
• DE GROOT H, SIES H: Role of reactive oxygen species in flbrogenesis. In: Molecular and Cell Biology of Liver Fibro-genesis. Gressner AM, Ramadori G, (Eds.), Kluwer Academic Publishers, The Dordrecht, Netherlands. (1992):277–288.
   Google Scholar
• WU J, LIU P, ZHU J-L, LIU S-L, RATTAN S, ZERN MA: Endotoxin-induced nitric oxide production in rat he-patocytes and its role in necrosis and apoptosis. Hepa-tology (1998) 28:500A.
   Google Scholar
• WU J, PENG CQ: An experimental study of cytoprotec-live effect by prostaglandin E2 on CC14-induced liver injury in rat (in Chinese). Chin. J. Digest (1989) 9:184–185.
   Google Scholar
• ROSSER BG, GORES GJ: Liver cell necrosis: cellular mechanisms and clinical implications. Gastroenterol-ogy (1995) 108:252–275.
   PubMed Web of Science ®Google Scholar
• •Features and pathogenesis of hepatic necrosis and apopto-sis were compared, and various approaches for study of apoptosis were discussed in this review.
   Google Scholar
• SIMBULA G, GLASCOTT PA, AKITA S, HOEK JB, FARBER JL: Two mechanisms by which ATP depletion potenti-ates induction of the mitochondrial permeability tran-sition. Am. J. Physiol. (1997) 42:C479–C488.
   Google Scholar
• SUSIN SA, ZAMZAMI N, KROEMER G: Mitochondria as regulators of apoptosis: doubt no more. Biochim. Biocphys. Acta (1998) 1366:151–165.
   PubMed Web of Science ®Google Scholar
• ••A three-step model of apoptosis was proposed in this article:a premitochondrial phase during which signal transduction cascades or damage pathways are activated; a mitochondrial phase, during which mitochondrial membrane function is lost; and a post-mitochondrial phase, during which proteins released from mitochondria cause the activation of catabolic proteases and nucleases.
   Google Scholar
• HOEK JB, FARBER JL, THAMAS AP, WANG X: Calcium ion-dependent signalling and mitochondrial dysfunc-tion: mitochondrial calcium uptake during hormonal stimulation in intact liver cells and its implication for the mitochondrial permeability transition. Biochim. Biophys. Acta (1995)1271 :93–102.
   PubMed Web of Science ®Google Scholar
• NIEMINEN AL, PETRIE TG, LEMASTERS JJ, SELMAN WR: Cyclosporin A delays mitochondrial depolarization induced by N-methyl-D-aspartate in cortical neurons: evidence of the mitochondrial permeability transi-tion. Neuroscience (1996) 75:993–997.
   PubMed Web of Science ®Google Scholar
• CAI J, YANG J, JONES DP: Mitochondrial control of apoptosis: the role of cytochrome C. Biochim. Biophys. Acta (1998) 1366:139–149.
   PubMed Web of Science ®Google Scholar
• ••Mitochondrial cytochrome C (MCC) has been found to havedual functions in controlling both cellular energetic metabo-lism and apoptosis. This article discusses the role of MCC re-lease in the mediation of apoptosis.
   Google Scholar
• AUGUILAR HI, BOTLA R, ARORA AS, BRONK SF, GORES GJ: Induction of the mitochondrial permeability tran-sition by protease activity in rats: a mechanism of he-patocyte necrosis. Gastroenterology (1996) 110:558–566.
   PubMed Web of Science ®Google Scholar
• GORES GJ, MIYOSHI H, BOTLA R, AGUILAR HI, BRONK SF: Induction of the mitochondrial permeability tran-sition as a mechanism of liver injury during cholesta-sis: potential role for mitochondrial proteases. Biochim. Biophys. Acta (1998) 1366:167–175.
   PubMed Web of Science ®Google Scholar
• ••This article reviews investigations of the role of MPT in he-patocyte necrosis during cholestasis, and the concept that endogenous mitochondrial protease activity may lead to the MPT.
   Google Scholar
• GLASCOTT PA, GILFOR E, FARBER JL: Relationship of the metabolism of vitamins C and E in cultured hepato-cytes treated with tert-butyl hydroperoxide. Mol. Phar-macol. (1995) 48:80–88.
   PubMed Web of Science ®Google Scholar
• NIEMINEN AL, BYME AM, HERMAN B, LEMASTERS JJ: Mi-tochondrial permeability transition in hepatocytes in-duced by t-bu0OH:NAD(1)1-1 reactive oxygen species. Am. J. Physiol. (1997) 272:C286–C294.
   Google Scholar
• LEMASTERS JJ, NEIMINEN AL, QIAN T et al.: The mito-chondrial permeability transition in cell death: a com-mon mechanism in necrosis, apoptosis and autophagy. Biochim. Biophys. Acta (1998) 1366:177–196.
   PubMed Web of Science ®Google Scholar
• ••This comprehensive review delineates the methods forstudy of MPT in hepatocytes and other cell types, the rela-tionship of MPT in apoptosis and necrosis, as well as potential therapeutic strategies for hepatotoxin-associated liver injury.
   Google Scholar
• TROST LC, LEMASTERS JJ: Role of the mitochondrial per-meability transition in salicylate toxicity to cultured rat hepatocytes: implications for the pathogenesis of Reye's syndrome. Toxicol. Appl. PharmacoL (1997) 147:431–441.
   PubMed Web of Science ®Google Scholar
• PASTORINO JG, WILHELM TJ, GLASCOTT PA, KOCSIS JJ, FARBER JL: Dexamethasone induces resistance to the lethal consequences of electron transport inhibition in cultured hepatocytes. Arch. Biochem. Biophys. (1995) 318:175–181.
   PubMed Web of Science ®Google Scholar
• GOMEZ J, GARCIA-DOMINGO D, MATINEZ-A C, RE-BOLLO A: Role of NF-kappa B in the control of apopto-sis and proliferative response in 11.-2-responsive T cells. Front BioscL (1997) 2:49–60.
   Google Scholar
• BARNES PJ, KARIN M: Nuclear factor-KB - a pivotal tran-scription factor in chronic inflammatory disease. New Engl. J. Med. (1997) 336:1066–1071.
   PubMed Web of Science ®Google Scholar
• ••An summary of the role of NF-icB in intracellular signalingsand molecular responses, as well as its clinical relevance and its therapeutic potential.
   Google Scholar
• PALOMBELLA V, RANDO IJ, GOLDBERG AL, MANIATIS T: The ubiquitin-proteasome pathway is required for processing the NE-031 precursor protein and the acti-vation of NF-03. Cell (1994) 78:773–785.
   PubMed Web of Science ®Google Scholar
• LIN YC, BROWN K, SIEBENLIST U: Activation of NF-kappa B requires proteolysis of the inhibitor kBa: signal-induced phosphorylation of bcBa alone does not release active NF-03. Proc. Natl. Acad. ScL USA (1995) 92:552–556.
   PubMed Web of Science ®Google Scholar
• MEYER R, HATADA EN, HOHMANN HP, LAHM HW, VAN LOON APGM, SCHEIDEREIT C: Cloning of the DNA-binding subunit of human nuclear factor 03: the level of its mRNA is strongly regulated by phorbol ester or tumor necrosis factor-alpha. Proc. Natl. Acad. ScL USA (1991) 88:966–970.
   PubMed Web of Science ®Google Scholar
• WEBBER EM, BRUIX J, PIERCE RH, FAUSTO N: Tumor ne-crosis factor primes hepatocytes for DNA replication in the rat. Hepatology (1998) 28:1226–1234.
   PubMed Web of Science ®Google Scholar
• TRAN-THI TA, DECKER K, BAEUERLE PA: Differential ac-tivation of transcription factors NF-03 and AP-1 in rat liver macrophages. Hepatology (1995) 22:613–619.
   PubMed Web of Science ®Google Scholar
• AUPHAN N, DIDONATO JA, ROSETTE C, HELMBERG A, KARM M: Immunosuppression by glucocorticoids: in-hibition of NF-03 activity through induction of la synthesis. Science (1995) 270:286–289.
   PubMed Web of Science ®Google Scholar
• WANG JY, GUO JS, LI H, LIU SL, ZERN MA: Inhibitory ef-fect of glycyrrhizin on NF-kappa B binding activity in CC14-plus ethanol-induced liver cirrhosis in rats. Liver (1998) 18:180–185.
   PubMedGoogle Scholar
• VAN ANTWERP DJ, MARTIN SJ, KAFRI T, GREEN DR, VERMA IM: Suppression of TNF-a-induced apoptosis by NF-03. Science (1996) 274:787–789.
   PubMed Web of Science ®Google Scholar
• BEG AA, SHA WC, BRONSON RT, GHOSH S, BALTIMORE D: Embryonic lethality and liver degeneration in mice lacking the RelA component of NE-KB. Nature (1995) 376:167–170.
   PubMed Web of Science ®Google Scholar
• BELLAS RE, FITZGERALD MJ, FAUSTO N, SONENSHEIN GE: Inhibition of NF-KB activity induces apoptosis in murine hepatocytes. Am. J. Pathol. (1997) 151:891–896.
   PubMed Web of Science ®Google Scholar
• ABBADIE C, KABRUN N, BOUALI F et al.: High levels of c-rel expression are associated with programmed cell death in the developing avian embryo and in bone marrow cells in vitro. Cell (1993) 75:899–912.
   PubMed Web of Science ®Google Scholar
• KRAJCOVICOVA-KUDLACKOVA M, OZDIN L: Effect of fatty acid composition, cadmium and vitamin E intake on prooxidative-antioxidative state of rat liver. Veterin. Med. (1995) 40:293–298.
   PubMed Web of Science ®Google Scholar
• MORGAN MY: The treatment of alcoholic hepatitis. Al-cohol Alcoholism (1996) 31:117–134.
   PubMed Web of Science ®Google Scholar
• WU J, DANIELSSON A: Inhibition of hepatic fibrogene-sis, a review of pharmacological candidates. Scand. J. Gastroenterol. (1994) 29:385–391.
   PubMed Web of Science ®Google Scholar
• MATO JM, ALVAREZ L, ORTIZ P, PAJARES MA: S-Adenosylmethionine synthesis: molecular mecha-nisms and clinical implications. Pharmacol. Ther. (1997) 73:265–280.
   PubMed Web of Science ®Google Scholar
• •The beneficial roles of S-adenosyl-L-methionine for chronic liver diseases have been summarised in this review.
   Google Scholar
• OSMAN E, OWEN JS BURROUGHS AK: S-Adenosyl-L-methionine: a new therapeutic agent in liver disease? Aliment. Pharmacol. Ther. (1993) 7:21–28.
   Web of Science ®Google Scholar
• HEUMAN DM: Hepatoprotective properties of ursode-oxycholic acid. Gastroenterology (1993) 104:1865–1870.
   PubMed Web of Science ®Google Scholar
• LINDOR KD, DICKSON ER, BALDUS WP et al: Ursodeoxy-cholic acid in the treatment of primary biliary cirrho-sis. Gastroenterology (1994) 106:1284–1290.
   PubMed Web of Science ®Google Scholar
• STOTT I, MURTHY A, ROBINSON A, THOMAS NW, FRY JR: Low-dose diethyldithiocarbamate attenuates the hepa-totoxicity of 1,3-dichloro-2-propanol and selectively 3inhibits CYP2E1 activity in the rat. Human Exp. Toxi-col. (1997) 16:262–266.
   PubMed Web of Science ®Google Scholar
• NIKNAHAD H, KHAN S, O'BRIEN PJ Hepatocyte injury resulting from the inhibition of mitochondrial respi-ration at low oxygen concentrations involves reductive stress and oxygen activation. Chem. Biol. In-teract. (1995) 98:27–44.
   Google Scholar
• GEBHARDT R: Antioxidative and protective properties of extracts from leaves of the artichoke (Cynara scoly-mus L.) against hydroperoxide-induced oxidative stress in cultured rat hepatocytes. Toxicol. App. Pharma-col. (1997) 144:279–286.
   Google Scholar
• KOSTRUBSKY VE, SZAKACS JG, JEFFERY EH et al.: Protec-tion of ethanol-mediated acetaminophen hepatotoxic-ity by triacetyloleandomycin, a specific inhibitor of CYP3A. Ann. Clin. Lab. Sci. (1997) 27:57–62.
   PubMed Web of Science ®Google Scholar
• GREENWALD RA: Superoxide dismutase and catalase as therapeutic agents for human disease, a critical re-view. Free Rad. Biol. Med. (1990) 8:210–209.
   Google Scholar
• NATAE D, YAMAMOTO K, YOSHIJI H, KINOGASA T, MA-RUYAMA H, FARBER JJ, KONISHI Y: Liposome-encapsulated superoxide dismutase prevents liver ne-crosis induced by acetaminophen. Am. J. Pathol (1990) 136:787–795.
   PubMed Web of Science ®Google Scholar
• WU J, LIU P, ZHU J-L, MADDUKURI S, ZERN MA: Increased liver up-take of liposomes and improved targeting effi-cacy by labeling with asialofetuin in rodents. Hepatol-ogy (1998) 27:772–778.
   PubMed Web of Science ®Google Scholar
• •The study showed that asialofetuin-labelled liposomes have a better targeting efficacy to hepatocytes than conventional liposomes.
   Google Scholar
• WU J, ZERN MA: Modification of liposomes for liver tar-geting. J. Hepatol. (1996) 24:757–763.
   PubMed Web of Science ®Google Scholar
• WU J, WU GY, ZERN MA: The prospects of hepatic drug delivery and gene therapy. Exp. Opin. Invest. Drugs (1998) 7:1795–1817.
   PubMedGoogle Scholar
• ••A comprehensive review of recent developments in hepaticdrug delivery and gene therapy. Jian Wu", Ake Danielsson2, Mark A Zern1 tAuthor for correspondence
   Google Scholar