Ursodeoxycholic Acid Protects Hepatocytes against Oxidative Injury via Induction of Antioxidants

Mitsuyoshi, Hironori; Nakashima, Tomoki; Sumida, Yoshio; Yoh, Takaharu; Nakajima, Yoshiki; Ishikawa, Hiroki; Inaba, Koji; Sakamoto, Yoshikuni; Okanoue, Takeshi; Kashima, Kei

doi:10.1006/bbrc.1999.1403

Cited by 147 publications

(90 citation statements)

References 35 publications

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“…Several reports described a role for the putative beneficial effect of UDCA exerted at the level of mitochondrial function, where UDCA prevents the impairment of mitochondrial function induced by toxic bile acids (Gores et al, 1998;Rodrigues et al, 1998). It has also been reported that UDCA could exert a cytoprotective action related to oxidative injury and antioxidant systems (Mitsuyoshi et al, 1999). However, other studies do not show cytoprotection by UDCA against toxic bile acids at the level of mitochondria or cell function (Krahenbuhl et al, 1994;Hillaire et al, 1995;Rolo et al, 2000).…”

Section: Resultsmentioning

confidence: 99%

Interactions of combined bile acids on hepatocyte viability: cytoprotection or synergism

2002

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Cholestasis results from hepatocyte dysfunction due to the accumulation of bile acids in the cell, many of which are known to be cytotoxic. Recent evidence implicates competitive antagonism of key cytotoxic responses as the mechanism by which certain therapeutic bile acids might afford cytoprotection against cholestasis. In this work, we compare the relative cytotoxicity of bile acids in terms of dose-and time-dependence. To better elucidate the controversy related to the therapeutic use of ursodeoxycholate (UDCA) in cholestatic patients, we also evaluated the effects of bile acid combinations. Viability of Wistar rat hepatocytes in primary culture was measured by LDH leakage after 12 and 24 h exposure of cells to the various bile acids. All unconjugated bile acids caused a dose-dependent decrease in cell viability. The tauro-and glyco-conjugates of chenodeoxycholate (CDCA) and UDCA were all less toxic than the corresponding unconjugated form. Although relatively non-toxic, UDCA caused synergistic cell killing by lithocholate (LCA), CDCA, glyco-CDCA (GCDC) and tauro-CDCA (TCDC). Glycoursodeoxycholate decreased the toxicity of GCDC, but potentiated the toxicity of unconjugated CDCA and LCA. The tauro-conjugate of UDCA had no significant effect. These data suggest that at cholestatic concentrations, bile acid-induced cell death correlates with the degree of lipophilicity of individual bile acids. However, these results indicate that the reported improvement of biochemical parameters in cholestatic patients treated with UDCA is not due to a direct effect of UDCA on hepatocyte viability. Therefore, any therapeutic effect of UDCA must be secondary to some other process, such as altered membrane transport or nonparenchymal cell function.

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Section: Resultsmentioning

confidence: 99%

Interactions of combined bile acids on hepatocyte viability: cytoprotection or synergism

2002

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“…One paper reported a fall in both GCLC and GCLM mRNA levels (Serviddio et al, 2004). Interestingly, ursodeoxycholic acid, the only treatment approved by the Food and Drug Administration for the treatment of primary biliary cirrhosis, a chronic cholestatic disorder, was shown to prevent the fall in GCL expression during chronic cholestasis (Serviddio et al, 2004) and increase GCL expression in cultured rat hepatocytes (Mitsuyoshi et al, 1999). The molecular mechanisms for changes in GCL expression during cholestasis or in response to ursodeoxycholic acid treatment remain unknown.…”

Section: Cholestasismentioning

confidence: 99%

Regulation of glutathione synthesis

Lu¹

2009

Molecular Aspects of Medicine

1,600

765

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Glutathione (GSH) is a ubiquitous intracellular peptide with diverse functions that include detoxification, antioxidant defense, maintenance of thiol status, and modulation of cell proliferation. GSH is synthesized in the cytosol of all mammalian cells in a tightly regulated manner. The major determinants of GSH synthesis are the availability of cysteine, the sulfur amino acid precursor, and the activity of the rate-limiting enzyme, glutamate cysteine ligase (GCL). GCL is composed for a catalytic (GCLC) and modifier (GCLM) subunit and they are regulated at multiple levels and at times differentially. The second enzyme of GSH synthesis, GSH synthase (GS) is also regulated in a coordinated manner as GCL subunits and its up-regulation can further enhance the capacity of the cell to synthesize GSH. Oxidative stress is well known to induce the expression of GSH synthetic enzymes. Key transcription factors identified thus far include Nrf2/Nrf1 via the antioxidant response element (ARE), activator protein-1 (AP-1) and nuclear factor κ B (NFκB). Dysregulation of GSH synthesis is increasingly being recognized as contributing to the pathogenesis of many pathological conditions. These include diabetes mellitus, pulmonary fibrosis, cholestatic liver injury, endotoxemia and drug-resistant tumor cells. Manipulation of the GSH synthetic capacity is an important target in the treatment of many of these disorders.

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“…[4][5][6][7] Ursodeoxycholic acid (UDCA) (Figure 1) is a nontoxic bile acid that has been reported to protect hepatocytes, hepatoma cells, osteogenic sarcomas and HeLa cells from apoptosis induced by okadaic acid, hydrogen peroxide, ethanol, and more hydrophobic bile acids, for example, DCA. [8][9][10][11][12][13][14][15] Other investigators found that UDCA promoted apoptosis in some systems. 16,17 These diverse reports prompted an examination of the effects of UDCA on PDT-induced apoptosis in cell culture.…”

Section: Introductionmentioning

confidence: 99%

A mechanism for the proapoptotic activity of ursodeoxycholic acid: effects on Bcl-2 conformation

2004

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Ursodeoxycholic acid (UDCA), a relatively nontoxic bile acid, enhanced the apoptotic response of tumor cells to both photosensitizers that cause photodamage to Bcl-2 and to the nonpeptidic Bcl-2/Bcl-x L antagonist HA14-1. The latter agent binds to the surface pocket formed by the BH1, BH2 and BH3 domains of Bcl-2 and Bcl-x L . Fluorescence polarization studies indicated that affinity of HA14-1 for Bcl-2 was enhanced in the presence of UDCA. Moreover, Bcl-2 photodamage was promoted by UDCA using a photosensitizing agent with affinity for the endoplasmic reticulum, a site of Bcl-2 localization. Fluorescence resonance energy transfer (FRET) studies revealed that the proximity of Bcl-2 to a hydrophobic photosensitizing agent embedded in liposomes was enhanced by UDCA. Since photodamage will occur only if a protein is in close contact with a photosensitizing agent, we propose that these findings support the hypothesis that UDCA causes a conformational change in Bcl-2, promoting HA14-1 binding and enhancing affinity for certain membrane-bound photosensitizers. Cell Death and Differentiation (2004) 11, 906-914. doi:10.1038/sj.cdd.4401433 Keywords: apoptosis; Bcl-2; CPO; NPe6; SnET2; photodynamic therapy (PDT)Abbreviations: CPO, 9-capronyloxy-tetrakis(methoxyethyl) porphycene; DCA, deoxycholic acid; DEVD-R110, asp-glu-valasp-rhodamine 110 (fluorogenic caspase-3 substrate); ER, endoplasmic reticulum; flu-Bak, 5-carboxyfluorecein coupled to the N terminus of a peptide GQVGRQLAIIGDDINR derived from the BH3 domain of Bak; HA14-1, ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; HO342, Höchst dye HO33342; mTHPC, meta-(tetrahydroxyphenyl) chlorin; NPe6, N-aspartyl chlorin e6; P, fluorescence polarization value; PDT, photodynamic therapy; SnET2, tin etiopurpurin; UDCA, ursodeoxycholic acid.

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Ursodeoxycholic Acid Protects Hepatocytes against Oxidative Injury via Induction of Antioxidants

Cited by 147 publications

References 35 publications

Interactions of combined bile acids on hepatocyte viability: cytoprotection or synergism

Interactions of combined bile acids on hepatocyte viability: cytoprotection or synergism

Regulation of glutathione synthesis

A mechanism for the proapoptotic activity of ursodeoxycholic acid: effects on Bcl-2 conformation

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