• 1
    Kaplowitz N, Javitt N, Harber LC. Isolation of erythrocytes with normal protoporphyrin levels in erythropoietic protoporphyria. N Engl J Med 1968; 278: 1077-1081.
  • 2
    Kaplowitz N, Javitt N, Kappas A. Coproporphyrin I and 3 excretion in bile and urine. J Clin Invest 1972; 51: 2895-2899.
  • 3
    Kaplowitz N, Javitt NB. Quantitative analysis of unconjugated and conjugated bile acids in duodenal fluid by densitometry after paper electrophoresis. J Lipid Res 1973; 14: 224-228.
  • 4
    Kaplowitz N, Kok E, Javitt NB. Postprandial serum bile acid for the detection of hepatobiliary disease. JAMA 1973; 225: 292-293.
  • 5
    Kaplowitz N, Percy-Robb IW, Javitt NB. Role of hepatic anion-binding protein in bromsulphthalein conjugation. J Exp Med 1973; 138: 483-487.
  • 6
    Kaplowitz N, Kuhlekamp J, Clifton G. Drug induction of hepatic glutathione S-transferases in male and female rats. Biochem J 1975; 146: 351-356.
  • 7
    Kaplowitz N. Enzymatic thiolysis of azathioprine in vitro. Biochem Pharmacol 1976; 25: 2421-2426.
  • 8
    Kaplowitz N. Interaction of azathioprine and glutathione in the liver of the rat. J Pharmacol Exp Ther 1977; 200: 479-486.
  • 9
    Sugiyama Y, Yamada T, Kaplowitz N. Newly identified bile acid binders in rat liver cytosol. Purification and comparison with glutathione S-transferases. J Biol Chem 1983; 258: 3602-3607.
  • 10
    Stolz A, Sugiyama Y, Kuhlenkamp J, Kaplowitz N. Identification and purification of 36 kDa bile acid binder in human hepatic cytosol. FEBS Lett 1984; 177: 31-35.
  • 11
    Stolz A, Takikawa H, Sugiyama Y, Kuhlenkamp J, Kaplowitz N. 3 Alpha-hydroxysteroid dehydrogenase activity of the Y' bile acid binders in rat liver cytosol. Identification, kinetics, and physiologic significance. J Clin Invest 1987; 79: 427-434.
  • 12
    Takikawa H, Stolz A, Kaplowitz N. Cyclical oxidation-reduction of the C3 position on bile acids catalyzed by rat hepatic 3 alpha-hydroxysteroid dehydrogenase. I. Studies with the purified enzyme, isolated rat hepatocytes, and inhibition by indomethacin. J Clin Invest 1987; 80: 852-860.
  • 13
    Takikawa H, Ookhtens M, Stolz A, Kaplowitz N. Cyclical oxidation-reduction of the C3 position on bile acids catalyzed by 3 alpha-hydroxysteroid dehydrogenase. II. Studies in the prograde and retrograde single-pass, perfused rat liver and inhibition by indomethacin. J Clin Invest 1987; 80: 861-866.
  • 14
    Takikawa H, Stolz A, Sugiyama Y, Yoshida H, Yamanaka M, Kaplowitz N. Relationship between the newly identified bile acid binder and bile acid oxidoreductases in human liver. J Biol Chem 1990; 265: 2132-2136.
  • 15
    Eberle D, Clarke R, Kaplowitz N. Rapid oxidation in vitro of endogenous and exogenous glutathione in bile of rats. J Biol Chem 1981; 256: 2115-2117.
  • 16
    Aw TY, Ookhtens M, Kaplowitz N. Inhibition of glutathione efflux from isolated rat hepatocytes by methionine. J Biol Chem 1984; 259: 9355-9358.
  • 17
    Ookhtens M, Hobdy K, Corvasce MC, Aw TY, Kaplowitz N. Sinusoidal efflux of glutathione in the perfused rat liver. Evidence for a carrier-mediated process. J Clin Invest 1985; 75: 258-265.
  • 18
    Aw TY, Ookhtens M, Ren C, Kaplowitz N. Kinetics of glutathione efflux from isolated rat hepatocytes. Am J Physiol 1986; 250( pt 1): G236-G243.
  • 19
    Aw TY, Ookhtens M, Kaplowitz N. Mechanism of inhibition of glutathione efflux by methionine from isolated rat hepatocytes. Am J Physiol 1986; 251( pt 1): G354-G361.
  • 20
    Ookhtens M, Lyon I, Fernandez-Checa J, Kaplowitz N. Inhibition of glutathione efflux in the perfused rat liver and isolated hepatocytes by organic anions and bilirubin. Kinetics, sidedness, and molecular forms. J Clin Invest 1988; 82: 608-616.
  • 21
    García-Ruiz C, Fernández-Checa JC, Kaplowitz N. Bidirectional mechanism of plasma membrane transport of reduced glutathione in intact rat hepatocytes and membrane vesicles. J Biol Chem 1992; 267: 22256-22264.
  • 22
    Lu SC, Ge JL, Huang HY, Kuhlenkamp J, Kaplowitz N. Thiol-disulfide effects on hepatic glutathione transport. Studies in cultured rat hepatocytes and perfused livers. J Clin Invest 1993; 92: 1188-1197.
  • 23
    Lu SC, Kuhlenkamp J, Ge JL, Sun WM, Kaplowitz N. Specificity and directionality of thiol effects on sinusoidal glutathione transport in rat liver. Mol Pharmacol 1994; 46: 578-585.
  • 24
    Fernandez-Checa JC, Ookhtens M, Kaplowitz N. Effect of chronic ethanol feeding on rat hepatocytic glutathione. Compartmentation, efflux, and response to incubation with ethanol. J Clin Invest 1987; 80: 57-62.
  • 25
    Fernandez-Checa JC, Ookhtens M, Kaplowitz N. Effects of chronic ethanol feeding on rat hepatocytic glutathione. Relationship of cytosolic glutathione to efflux and mitochondrial sequestration. J Clin Invest 1989; 83: 1247-1252.
  • 26
    Fernández-Checa JC, García-Ruiz C, Ookhtens M, Kaplowitz N. Impaired uptake of glutathione by hepatic mitochondria from chronic ethanol-fed rats. Tracer kinetic studies in vitro and in vivo and susceptibility to oxidant stress. J Clin Invest 1991; 87: 397-405.
  • 27
    Hirano T, Kaplowitz N, Tsukamoto H, Kamimura S, Fernandez-Checa JC. Hepatic mitochondrial glutathione depletion and progression of experimental alcoholic liver disease in rats. HEPATOLOGY 1992; 16: 1423-1427.
  • 28
    García-Ruiz C, Morales A, Ballesta A, Rodés J, Kaplowitz N, Fernández-Checa JC. Effect of chronic ethanol feeding on glutathione and functional integrity of mitochondria in periportal and perivenous rat hepatocytes. J Clin Invest 1994; 94: 193-201.
  • 29
    Lu SC, Garcia-Ruiz C, Kuhlenkamp J, Ookhtens M, Salas-Prato M, Kaplowitz N. Hormonal regulation of glutathione efflux. J Biol Chem 1990; 265: 16088-16095.
  • 30
    Lu SC, Kuhlenkamp J, Garcia-Ruiz C, Kaplowitz N. Hormone-mediated down-regulation of hepatic glutathione synthesis in the rat. J Clin Invest 1991; 88: 260-269.
  • 31
    Lu SC, Ge JL, Kuhlenkamp J, Kaplowitz N. Insulin and glucocorticoid dependence of hepatic gamma-glutamylcysteine synthetase and glutathione synthesis in the rat. Studies in cultured hepatocytes and in vivo. J Clin Invest 1992; 90: 524-532.
  • 32
    DeLeve LD, Wang X, Kuhlenkamp JF, Kaplowitz N. Toxicity of azathioprine and monocrotaline in murine sinusoidal endothelial cells and hepatocytes: the role of glutathione and relevance to hepatic venoocclusive disease. HEPATOLOGY 1996; 23: 589-599.
  • 33
    DeLeve LD, Wang X, Kaplowitz N, Shulman HM, Bart JA, van der Hoek A. Sinusoidal endothelial cells as a target for acetaminophen toxicity. Direct action versus requirement for hepatocyte activation in different mouse strains. Biochem Pharm 1997; 53: 1339-1345.
  • 34
    Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB. Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J Pharmacol Exp Ther 1973; 187: 211-217.
  • 35
    Matsumaru K, Ji C, Kaplowitz N. Mechanisms for sensitization to TNF-induced apoptosis by acute glutathione depletion in murine hepatocytes. HEPATOLOGY 2003; 37: 1425-1434.
  • 36
    Nagai H, Matsumaru K, Feng G, Kaplowitz N. Reduced glutathione depletion causes necrosis and sensitization to tumor necrosis factor-α-induced apoptosis in cultured mouse hepatocytes. HEPATOLOGY 2002; 36: 55-64.
  • 37
    Han D, Hanawa N, Saberi B, Kaplowitz N. Hydrogen peroxide and redox modulation sensitize primary mouse hepatocytes to TNF-induced apoptosis. Free Radic Biol Med 2006; 41: 627-639.
  • 38
    Lou H, Kaplowitz N. Glutathione depletion down-regulates tumor necrosis factor α-induced NF-κB activity via IκB kinase-dependent and -independent mechanisms. J Biol Chem 2007; 282: 29470-29481.
  • 39
    Gunawan BK, Liu ZX, Han D, Hanawa N, Gaarde WA, Kaplowitz N. c-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity. Gastroenterology 2006; 131: 165-178.
  • 40
    Shinohara M, Ybanez MD, Win S, Than TA, Jain S, Gaarde WA, et al. Silencing glycogen synthase kinase-3beta inhibits acetaminophen hepatotoxicity and attenuates JNK activation and loss of glutamate cysteine ligase and myeloid cell leukemia sequence 1. J Biol Chem 2010; 285: 8244-8255.
  • 41
    Hanawa N, Shinohara M, Saberi B, Gaarde WA, Han D, Kaplowitz N. Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury. J Biol Chem 2008; 283: 13565-13577.
  • 42
    Win S, Than TA, Han D, Petrovic LM, Kaplowitz N. c-Jun N-terminal kinase (JNK)-dependent acute liver injury from acetaminophen or tumor necrosis factor (TNF) requires mitochondrial Sab protein expression in mice. J Biol Chem 2011; 286: 35071-35078.
  • 43
    Chambers JW, LoGrasso PV. Mitochondrial c-Jun N-terminal kinase (JNK) signaling initiates physiological changes resulting in amplification of reactive oxygen species generation. J Biol Chem 2011; 286: 16052-16062.
  • 44
    García-Ruiz C, Morales A, Ballesta A, Rodés J, Kaplowitz N, Fernández-Checa J. Effect of chronic ethanol feeding on glutathione and functional integrity of mitochondria in periportal and perivenous rat hepatocytes. J Clin Invest 1994; 94: 193-201.
  • 45
    García-Ruiz C, Morales A, Colell A, Ballesta A, Rodés J, Kaplowitz N, et al. Feeding S-adenosyl-L-methionine attenuates both ethanol-induced depletion of mitochondrial glutathione and mitochondrial dysfunction in periportal and perivenous rat hepatocytes. HEPATOLOGY 1995; 21: 207-214.
  • 46
    García-Ruiz C, Colell A, Morales A, Kaplowitz N, Fernández-Checa JC. Role of oxidative stress generated from the mitochondrial electron transport chain and mitochondrial glutathione status in loss of mitochondrial function and activation of transcription factor nuclear factor-kappa B: studies with isolated mitochondria and rat hepatocytes. Mol Pharmacol 1995; 48: 825-834.
  • 47
    Colell A, García-Ruiz C, Morales A, Ballesta A, Ookhtens M, Rodés J, et al. Transport of reduced glutathione in hepatic mitochondria and mitoplasts from ethanol-treated rats: effect of membrane physical properties and S-adenosyl-L-methionine. HEPATOLOGY 1997; 26: 699-708.
  • 48
    Colell A, García-Ruiz C, Miranda M, Ardite E, Marí M, Morales A, et al. Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor. Gastroenterology 1998; 115: 1541-1551.
  • 49
    Colell A, Coll O, García-Ruiz C, París R, Tiribelli C, Kaplowitz N, et al. Tauroursodeoxycholic acid protects hepatocytes from ethanol-fed rats against tumor necrosis factor-induced cell death by replenishing mitochondrial glutathione. HEPATOLOGY 2001; 34: 964-971.
  • 50
    Lluis JM, Colell A, García-Ruiz C, Kaplowitz N, Fernández-Checa JC. Acetaldehyde impairs mitochondrial glutathione transport in HepG2 cells through endoplasmic reticulum stress. Gastroenterology 2003; 124: 708-724.
  • 51
    Coll O, Colell A, García-Ruiz C, Kaplowitz N, Fernández-Checa JC. Sensitivity of the 2-oxoglutarate carrier to alcohol intake contributes to mitochondrial glutathione depletion. HEPATOLOGY 2003; 38: 692-702.
  • 52
    Ji C, Kaplowitz N. Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice. Gastroenterology 2003; 124: 1488-1499.
  • 53
    Ji C, Mehrian-Shai R, Chan C, Hsu YH, Kaplowitz N. Role of CHOP in hepatic apoptosis in the murine model of intragastric ethanol feeding. Alcohol Clin Exp Res 2005; 29: 1496-1503.
  • 54
    Ji C, Chan C, Kaplowitz N. Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model. J Hepatol 2006; 45: 717-724.
  • 55
    Ji C, Shinohara M, Kuhlenkamp J, Chan C, Kaplowitz N. Mechanisms of protection by the betaine-homocysteine methyltransferase/betaine system in HepG2 cells and primary mouse hepatocytes. HEPATOLOGY 2007; 46: 1586-1596.
  • 56
    Ji C, Shinohara M, Vance D, Than TA, Ookhtens M, Chan C, et al. Effect of transgenic extrahepatic expression of betaine-homocysteine methyltransferase on alcohol or homocysteine-induced fatty liver. Alcohol Clin Exp Res 2008; 32: 1049-1058.
  • 57
    Shinohara M, Ji C, Kaplowitz N. Differences in betaine-homocysteine methyltransferase expression, endoplasmic reticulum stress response, and liver injury between alcohol-fed mice and rats. HEPATOLOGY 2010; 51: 796-805.
  • 58
    Ji C, Kaplowitz N, Lau MY, Kao E, Petrovic LM, Lee AS. Liver-specific loss of glucose-regulated protein 78 perturbs the unfolded protein response and exacerbates a spectrum of liver diseases in mice. HEPATOLOGY 2011; 54: 229-239.
  • 59
    Than TA, Lou H, Ji C, Win S, Kaplowitz N. Role of cAMP-responsive element-binding protein (CREB)-regulated transcription coactivator 3 (CRTC3) in the initiation of mitochondrial biogenesis and stress response in liver cells. J Biol Chem 2011; 286: 22047-22054.
  • 60
    Andrade RJ, Lucena MI, Kaplowitz N, García-Muņoz B, Borraz Y, Pachkoria K, et al. Outcome of acute idiosyncratic drug-induced liver injury: long-term follow-up in a hepatotoxicity registry. HEPATOLOGY 2006; 44: 1581-1588.
  • 61
    Lucena MI, Andrade RJ, Kaplowitz N, García-Cortes M, Fernández MC, Romero-Gomez M, et al.; for Spanish Group for the Study of Drug-Induced Liver Disease. Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex. HEPATOLOGY 2009; 49: 2001-2009.
  • 62
    Lucena MI, Kaplowitz N, Hallal H, Castiella A, García-Bengoechea M, Otazua P, et al. Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry: the dilemma of the relationship to autoimmune hepatitis. J Hepatol 2011; 55: 820-827.
  • 63
    Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Pe'er I, Floratos A, et al.; for DILIGEN Study and International SAE Consortium. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 2009; 41: 816-819.
  • 64
    Singer JB, Lewitzky S, Leroy E, Yang F, Zhao X, Klickstein L, et al. A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury. Nat Genet 2010; 42: 711-714.
  • 65
    Spraggs CF, Budde LR, Briley LP, Bing N, Cox CJ, King KS, et al. HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. J Clin Oncol 2011; 29: 667-673.
  • 66
    Hirata K, Takagi H, Yamamoto M, Matsumoto T, Nishiya T, Mori K, et al. Ticlopidine-induced hepatotoxicity is associated with specific human leukocyte antigen genomic subtypes in Japanese patients: a preliminary case-control study. Pharmacogenomics J 2008; 8: 29-33.
  • 67
    Lucena MI, Molokhia M, Shen Y, Urban TJ, Aithal GP, Andrade RJ, et al.; for Spanish DILI Registry, EUDRAGENE, DILIN, DILIGEN, and International SAEC. Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles. Gastroenterology 2011; 141: 338-347.
  • 68
    Kindmark A, Jawaid A, Harbron CG, Barratt BJ, Bengtsson OF, Andersson TB, et al. Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. Pharmacogenomics J 2008; 8: 186-195.
  • 69
    Uetrecht J. Immunoallergic drug-induced liver injury in humans. Semin Liver Dis 2009; 29: 383-392.
  • 70
    Littenberg G, Afroudakis A, Kaplowitz N. Common bile duct stenosis from chronic pancreatitis: a clinical and pathologic spectrum. Medicine (Baltimore) 1979; 58: 385-412.
  • 71
    Afroudakis A, Kaplowitz N. Liver histopathology in chronic common bile duct stenosis due to chronic alcoholic pancreatitis. HEPATOLOGY 1981; 1: 65-72.
  • 72
    Nathwani RA, Pais S, Reynolds TB, Kaplowitz N. Serum alanine aminotransferase in skeletal muscle diseases. HEPATOLOGY 2005; 41: 380-382.
  • 73
    Nathwani RA, Kumar SR, Reynolds TB, Kaplowitz N. Marked elevation in serum transaminases: an atypical presentation of choledocholithiasis. Am J Gastroenterol 2005; 100: 295-298.
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