Ursodeoxycholic acid in primary biliary cirrhosis improves glutathione status but fails to reduce lipid peroxidation

Pemberton, Philip W.; Aboutwerat, Ali; Smith, Alwyn; Warnes, Thomas W.

doi:10.1179/135100006x116600

Cited by 12 publications

(9 citation statements)

References 38 publications

(49 reference statements)

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“…UDCA is a potent inducer of the cytochrome NADPH-CYP-c-reductase, Aminopyrine N -demethylase CYP3A1/2, p-Nitrophenol hydroxylase CYP2E1, Ethoxycoumarin O -deethylase, Pentoxyresorufin O -dealkylase CYP2B1/2, Methoxyresorufin O-demethylase CYP1A2, Ethoxyresorufin O-deethylase CYP1A1, and Lauric acid hydroxylase CYP4A and inhibits their inactivation [113], raises glutathione plasma levels albeit still subnormal or within normal levels [114], and induces multidrug resistance protein 3, but not multidrug resistance protein 4, and 5. UDCA ability to counteract bile acid toxicity is compromised [115].…”

Section: Potentially Toxic Molecular Properties Of Udcamentioning

confidence: 99%

Molecular Mechanisms of Ursodeoxycholic Acid Toxicity & Side Effects: Ursodeoxycholic Acid Freezes Regeneration & Induces Hibernation Mode

Kotb

2012

IJMS

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Ursodeoxycholic acid (UDCA) is a steroid bile acid approved for primary biliary cirrhosis (PBC). UDCA is reported to have “hepato-protective properties”. Yet, UDCA has “unanticipated” toxicity, pronounced by more than double number of deaths, and eligibility for liver transplantation compared to the control group in 28 mg/kg/day in primary sclerosing cholangitis, necessitating trial halt in North America. UDCA is associated with increase in hepatocellular carcinoma in PBC especially when it fails to achieve biochemical response (10 and 15 years incidence of 9% and 20% respectively). “Unanticipated” UDCA toxicity includes hepatitis, pruritus, cholangitis, ascites, vanishing bile duct syndrome, liver cell failure, death, severe watery diarrhea, pneumonia, dysuria, immune-suppression, mutagenic effects and withdrawal syndrome upon sudden halt. UDCA inhibits DNA repair, co-enzyme A, cyclic AMP, p53, phagocytosis, and inhibits induction of nitric oxide synthatase. It is genotoxic, exerts aneugenic activity, and arrests apoptosis even after cellular phosphatidylserine externalization. UDCA toxicity is related to its interference with drug detoxification, being hydrophilic and anti-apoptotic, has a long half-life, has transcriptional mutational abilities, down-regulates cellular functions, has a very narrow difference between the recommended (13 mg/kg/day) and toxic dose (28 mg/kg/day), and it typically transforms into lithocholic acid that induces DNA strand breakage, it is uniquely co-mutagenic, and promotes cell transformation. UDCA beyond PBC is unjustified.

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Section: Potentially Toxic Molecular Properties Of Udcamentioning

confidence: 99%

Molecular Mechanisms of Ursodeoxycholic Acid Toxicity & Side Effects: Ursodeoxycholic Acid Freezes Regeneration & Induces Hibernation Mode

Kotb

2012

IJMS

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“…Human plasma [34], human serum [35] ORAC: oxygen radical absorbance capacity; ␤-PE: ␤-phycoerythrin; AUC: area under the curve that represents the analytical property monitored along time; BODIPY 581/591: 4,4-difluoro-5-(4-phenyl-1,3-butadienyl)-4-bora-3a,4a-diaza-s-indacene-3-undecanoic acid; TRAP: total radical-trapping antioxidant parameter; LDL: low-density lipoproteins; TOSC: total oxyradical scavenging capacity; KMBA: ␣-keto-␥-methiolbutyric acid; GC-FID: gas chromatography with flame ionization detector; CL: chemiluminescence. 123. In the competitive scheme, the target species, defined here as a compound that represents a biomolecule which may be attacked in vivo, and the antioxidant compounds compete for the reactive species (radical or non-radicals).…”

Section: Introductionmentioning

confidence: 99%

Methodological aspects about in vitro evaluation of antioxidant properties

Magalhães

Segundo

Reis

et al. 2008

Analytica Chimica Acta

614

404

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“…In addition to altering lipid composition, oxidative stress in PBC leads to accumulations of protein oxidative products and alterations in glutathione metabolism8. UDCA treatment of PBC seems to improve redox changes in serum and liver tissues9101112.…”

mentioning

confidence: 99%

Protection against oxidative stress mediated by the Nrf2/Keap1 axis is impaired in Primary Biliary Cholangitis

Wasik

Milkiewicz

Kempińska-Podhorodecka

et al. 2017

Sci Rep

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In response to oxidative stress, nuclear factor (erythroid-derived 2)-like2 (Nrf2) induces expression of cytoprotective genes. The Nrf2 pathway is controlled by microRNAs and Kelch-like ECH-associated protein1 (Keap1). Nrf2 is stabilized when Keap1 is degraded through the autophagy pathway in a p62-dependent manner. The inhibition of autophagy causes protein accumulation, and Keap1 is inactivated by binding to p62. We investigated the role of the Nrf2/Keap1 axis in the amelioration of oxidative stress in primary biliary cholangitis (PBC). Liver specimens from patients with PBC, with (n = 24) or without cirrhosis (n = 14), and from controls (n = 16) were used for molecular analyses. We found that Nrf2 protein levels were elevated in PBC compared to controls, but Nrf2 gene expression was significantly reduced in cirrhotic PBC. Nrf2 target gene products, HO-1 and GCLC proteins, were reduced compared to controls and reduction of Nrf2 gene expression was associated with elevated levels of microRNA-132 and microRNA-34a. Both Keap1 and p62 protein levels were substantially increased in PBC compared to controls. PBC was associated with reduced Nrf2 expression and autophagy deterioration and these impairments were more advanced in patients with cirrhosis. Aberrant Nrf2/Keap1 system integrity may affect self-defence mechanisms against oxidative stress in PBC.

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Ursodeoxycholic acid in primary biliary cirrhosis improves glutathione status but fails to reduce lipid peroxidation

Cited by 12 publications

References 38 publications

Molecular Mechanisms of Ursodeoxycholic Acid Toxicity & Side Effects: Ursodeoxycholic Acid Freezes Regeneration & Induces Hibernation Mode

Molecular Mechanisms of Ursodeoxycholic Acid Toxicity & Side Effects: Ursodeoxycholic Acid Freezes Regeneration & Induces Hibernation Mode

Methodological aspects about in vitro evaluation of antioxidant properties

Protection against oxidative stress mediated by the Nrf2/Keap1 axis is impaired in Primary Biliary Cholangitis

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