Galactosamine Prevents Ethinylestradiol-Induced Cholestasis

Crocenzi, Fernando A.; Pellegrino, J.; Catania, Viviana A.; Luquita, Marcelo G.; Roma, Marcelo G.; Mottino, Aldo D.; Pozzi, Enrique J. Sánchez

doi:10.1124/dmd.106.009308

Cited by 18 publications

(10 citation statements)

References 27 publications

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“…E 2 17G rapidly decreases bile flow, but its cholestatic effect is transient following a single dose, as recovery mechanisms occur almost simultaneously. These self-limiting mechanisms prevent the extrapolation of results from the acute model to the more common, long-lasting, clinical situations in which the liver is progressively and continuously exposed to cholestatic estrogen glucuronides, as is thought to occur in pregnancy and ethinylestradiol-induced cholestasis (4,28). We therefore developed an alternative cholestatic model in which decreased bile flow was sustained by repeated E 2 17G administration.…”

Section: Discussionmentioning

confidence: 97%

“…When administered intravenously as a bolus, the cholestatic effect of E 2 17G is virtually instantaneous, unlike that induced by nonconjugated estrogens, such as ethinylestradiol, which appear to require metabolic activation by glucuronidation to exert their cholestatic potential (4,28). This rapid mechanism makes E 2 17G a unique tool to discriminate initial events of the cholestatic phenomenon from long-lasting, secondary effects due to chronic accumulation of potentially toxic biliary compounds retained as a consequence of bile secretory failure, such as bile salts and bilirubin, that are cholestatic themselves (5,33).…”

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confidence: 95%

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Disruption of function and localization of tight junctional structures and Mrp2 in sustained estradiol-17β-d-glucuronide-induced cholestasis

Mottino

Hoffman²,

Crocenzi³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Estradiol-17beta-D-glucuronide (E(2)17G) induces immediate and profound but transient cholestasis in rats when administered as a single bolus dose. Here, we examined the consequence of sustained E(2)17G cholestasis and assessed the function and localization of the tight junctional proteins zonula occludens-1 (ZO-1) and occludin and of the canalicular transporter multidrug resistance-associated protein-2 (Mrp2). An initial dose of E(2)17G (15 mumol/kg iv) followed by five subsequent doses of 7.5 mumol/kg from 60 to 240 min induced a sustained 40-70% decrease in bile flow. Following their biliary retrograde administration, cholera toxin B subunit-FITC or horseradish peroxidase were detected at the sinusoidal domain, indicating opening of the paracellular route; this occurred as early as 15 min after the first dose as well as 15 min after the last dose of E(2)17G, but not following the administration of vehicle in controls. Localization of ZO-1 and occludin was only slightly affected under acute cholestatic conditions but was severely disrupted under sustained cholestasis, with their appearance suggesting a fragmented structure. Endocytic internalization of Mrp2 to the pericanalicular region was apparent 20 min after a single E(2)17G administration; however, Mrp2 was found more deeply internalized and partially redistributed to the basolateral membrane under sustained cholestasis. In conclusion, acute E(2)17G-induced cholestasis increased permeability of the tight junction, while sustained cholestasis provoked a significant redistribution of ZO-1, occludin, and Mrp2 in addition to increased permeability of the tight junction. Altered tight junction integrity likely contributes to impaired bile secretion and may be causally related to changes in Mrp2 localization.

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Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 95%

Disruption of function and localization of tight junctional structures and Mrp2 in sustained estradiol-17β-d-glucuronide-induced cholestasis

Mottino

Hoffman²,

Crocenzi³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Glucuronidation was found to be an important step in the pathogenesis of ethinylestradiol (EE)-induced cholestasis. When administered with d-GalN, there was an improvement in cholestasis because d-GalN decreases the UDP-GA availability required by EE 17 β-glucuronide, thus showing that these molecules are involved in cholestasis [54]. Hepatoxins, such as d-GalN, can cause inhibition of mature hepatocytes.…”

Section: General Mouse Models Of Liver Fibrosismentioning

confidence: 99%

Mouse Models of Liver Fibrosis Mimic Human Liver Fibrosis of Different Etiologies

et al. 2014

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The liver has the amazing capacity to repair itself after injury; however, the same processes that are involved in liver regeneration after acute injury can cause serious consequences during chronic liver injury. In an effort to repair damage, activated hepatic stellate cells trigger a cascade of events that lead to deposition and accumulation of extracellular matrix components causing the progressive replacement of the liver parenchyma by scar tissue, thus resulting in fibrosis. Although fibrosis occurs as a result of many chronic liver diseases, the molecular mechanisms involved depend on the underlying etiology. Since studying liver fibrosis in human subjects is complicated by many factors, mouse models of liver fibrosis that mimic the human conditions fill this void. This review summarizes the general mouse models of liver fibrosis and mouse models that mimic specific human disease conditions that result in liver fibrosis. Additionally, recent progress that has been made in understanding the molecular mechanisms involved in the fibrogenic processes of each of the human disease conditions is highlighted.

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“…Some information implicates Nrf2 in the regulation of Eh-1 expression. This evidence includes reduced basal mRNA expression of Eh-1 in multiple tissues of Nrf2-null mice (Ramos-Gomez et al , 2001; Crocenzi et al , 2006; Hu et al , 2006). Furthermore, a prototypical Nrf2 activator, oltipraz, induces Eh-1 in wild-type but not Nrf2-null mice, pointing to a role for Nrf2-mediated control (Ramos-Gomez et al , 2001).…”

Section: Introductionmentioning

confidence: 99%

Nrf2 the rescue: Effects of the antioxidative/electrophilic response on the liver

Klaassen¹,

Reisman²

2010

Toxicology and Applied Pharmacology

341

243

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Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that positively regulates the basal and inducible expression of a large battery of cytoprotective genes. These gene products include proteins that catalyze reduction reactions (NAD(P)H:quinone oxidoreductase 1, Nqo1), conjugation reactions (glutathione-S-transferases, Gsts and UDP-glucuronosyltransferases, Ugts), as well as the efflux of potentially toxic xenobiotics and xenobiotic conjugates (multidrug resistance-associated proteins, Mrps). The significance of Nrf2 in the liver has been established, as livers of Nrf2-null mice are more susceptible to various oxidative/electrophilic stress-induced pathologies than wild-type mice. In contrast, both pharmacological and genetic models of hepatic Nrf2 activation are protective against oxidative/electrophilic stress. Furthermore, because certain Nrf2-target genes in the liver could affect the distribution, metabolism, and excretion of xenobiotics, the effects of Nrf2 on the kinetics of drugs and other xenobiotics should also be considered, with a special emphasis on metabolism and excretion. Therefore, this review highlights the research that has contributed to the understanding of the importance of Nrf2 in toxicodynamics and toxicokinetics, especially that which pertains to the liver.

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Galactosamine Prevents Ethinylestradiol-Induced Cholestasis

Cited by 18 publications

References 27 publications

Disruption of function and localization of tight junctional structures and Mrp2 in sustained estradiol-17β-d-glucuronide-induced cholestasis

Disruption of function and localization of tight junctional structures and Mrp2 in sustained estradiol-17β-d-glucuronide-induced cholestasis

Mouse Models of Liver Fibrosis Mimic Human Liver Fibrosis of Different Etiologies

Nrf2 the rescue: Effects of the antioxidative/electrophilic response on the liver

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