A Critical Analysis of Experimental Animal Models of Sinusoidal Obstruction Syndrome

Kumar, Arvind; Pálek, Richard; Liška, Václav

doi:10.1016/j.jceh.2018.07.002

Cited by 7 publications

(8 citation statements)

References 54 publications

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“…These results suggested that sinusoidal injury happened in the model group, similar to human PA-HSOS, but the focus of this study was not on hepatocytes and their possible subcellular alterations. In a rat model of PA-HSOS using monocrotaline published by DeLeve et al [ 233 ], transmission and scanning electron microscopy showed early manifestation in the form of progressive injury to the sinusoidal wall, with the loss of sinusoidal lining cells, sinusoidal hemorrhage, and damage to the central vein epithelium, followed by coagulative necrosis of hepatocytes. This did not allow for more details of subcellular changes within the liver cells [ 233 ].…”

Section: Clinical Specifics Of Hsos Caused By 12-unsaturated Pasmentioning

confidence: 99%

“…In a rat model of PA-HSOS using monocrotaline published by DeLeve et al [ 233 ], transmission and scanning electron microscopy showed early manifestation in the form of progressive injury to the sinusoidal wall, with the loss of sinusoidal lining cells, sinusoidal hemorrhage, and damage to the central vein epithelium, followed by coagulative necrosis of hepatocytes. This did not allow for more details of subcellular changes within the liver cells [ 233 ]. The sequence of events suggests that PA-HSOS is primarily a vessel disease, followed by injurious manifestations of LSECs and liver cells [ 231 , 233 ].…”

Section: Clinical Specifics Of Hsos Caused By 12-unsaturated Pasmentioning

confidence: 99%

“…This did not allow for more details of subcellular changes within the liver cells [ 233 ]. The sequence of events suggests that PA-HSOS is primarily a vessel disease, followed by injurious manifestations of LSECs and liver cells [ 231 , 233 ]. Time line and mechanistic data of PA-HSOS, however, suggest that at first, the liver cells provide toxic, metabolically formed PAs that subsequently cross the plasma membranes of the hepatocytes and finally bind with proteins of non-liver cells, such as sinusoidal lining cells and LSECs.…”

Section: Clinical Specifics Of Hsos Caused By 12-unsaturated Pasmentioning

confidence: 99%

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Metabolic Toxification of 1,2-Unsaturated Pyrrolizidine Alkaloids Causes Human Hepatic Sinusoidal Obstruction Syndrome: The Update

Teschke

Noudeng

Quan

et al. 2021

IJMS

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Saturated and unsaturated pyrrolizidine alkaloids (PAs) are present in more than 6000 plant species growing in countries all over the world. They have a typical heterocyclic structure in common, but differ in their potential toxicity, depending on the presence or absence of a double bond between C1 and C2. Fortunately, most plants contain saturated PAs without this double bond and are therefore not toxic for consumption by humans or animals. In a minority of plants, however, PAs with this double bond between C1 and C2 exhibit strong hepatotoxic, genotoxic, cytotoxic, neurotoxic, and tumorigenic potentials. If consumed in error and in large emouns, plants with 1,2-unsaturated PAs induce metabolic breaking-off of the double bonds of the unsaturated PAs, generating PA radicals that may trigger severe liver injury through a process involving microsomal P450 (CYP), with preference of its isoforms CYP 2A6, CYP 3A4, and CYP 3A5. This toxifying CYP-dependent conversion occurs primarily in the endoplasmic reticulum of the hepatocytes equivalent to the microsomal fraction. Toxified PAs injure the protein membranes of hepatocytes, and after passing their plasma membranes, more so the liver sinusoidal endothelial cells (LSECs), leading to life-threatening hepatic sinusoidal obstruction syndrome (HSOS). This injury is easily diagnosed by blood pyrrolizidine protein adducts, which are perfect diagnostic biomarkers, supporting causality evaluation using the updated RUCAM (Roussel Uclaf Causality Assessment Method). HSOS is clinically characterized by weight gain due to fluid accumulation (ascites, pleural effusion, and edema), and may lead to acute liver failure, liver transplantation, or death. In conclusion, plant-derived PAs with a double bond between C1 and C2 are potentially hepatotoxic after metabolic removal of the double bond, and may cause PA-HSOS with a potential lethal outcome, even if PA consumption is stopped.

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Section: Clinical Specifics Of Hsos Caused By 12-unsaturated Pasmentioning

confidence: 99%

Section: Clinical Specifics Of Hsos Caused By 12-unsaturated Pasmentioning

confidence: 99%

Section: Clinical Specifics Of Hsos Caused By 12-unsaturated Pasmentioning

confidence: 99%

See 1 more Smart Citation

Metabolic Toxification of 1,2-Unsaturated Pyrrolizidine Alkaloids Causes Human Hepatic Sinusoidal Obstruction Syndrome: The Update

Teschke

Noudeng

Quan

et al. 2021

IJMS

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“…We suggest that the temporal relationship between the use of TA and SOS onset, rather, indicates a causal and not coincidental connection, although additional evidence is needed to prove TA treatment as a risk factor for SOS. Animal models of SOS provide a suitable platform for further studies [11,12]. Thus, the systemic application of TA to prevent bleeding complications early after myeloablative therapy should be carefully considered due to increasing evidence for a potentially additive role in SOS development [13], especially in patients with pre-existing high-risk features for hepatic SOS.…”

Section: Discussionmentioning

confidence: 99%

Sinusoidal Obstruction Syndrome Following Myeloablative Therapy and Tranexamic Acid Treatment for Hemorrhage in Two Patients with Neuroblastoma

et al. 2020

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Adverse thromboembolic events following administration of the anti-fibrinolytic agent tranexamic acid (TA), used to prevent/treat excessive blood loss, are rare. We present the clinical course of two young patients (22 and 56 months) receiving busulfan/melphalan (Bu/Mel) high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) to treat high-risk neuroblastoma, who developed hepatic sinusoidal obstruction syndrome (SOS) within 48 h after systemic TA treatment for a hemodynamically relevant hemorrhage. Defibrotide treatment resolved hepatic SOS, but the short time between TA administration and SOS onset suggests a causal association.

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“…Male Sprague–Dawley rats (175–250 g, n = 4) had an intragastric administration of MCT (160 mg/kg, Sigma, Buchs, Switzerland) while 5 additional normal (Nl) rats had an intragastric administration of saline solution [ 7 , 28 ]. MCT livers were isolated and perfused 18 days after gavage.…”

Section: Methodsmentioning

confidence: 99%

Monocrotaline Toxicity Alters the Function of Hepatocyte Membrane Transporters in Rats

Pastor

Vilgrain

2022

IJMS

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Pyrrolizidine alkaloid monocrotaline (MCT) induces sinusoidal obstruction syndrome (SOS) in rats characterised by a sinusoidal congestive obstruction. Additionally, MCT administration decreases the biliary excretion of gadobenate dimeglumine (BOPTA), a hepatobiliary substrate used in clinical imaging. BOPTA crosses hepatocyte membranes through organic anion transporting polypeptides, multidrug-resistance-associated protein 2, and Mrp3/4 transporters, and a modified function of these transporters is likely to explain the decreased biliary excretion. This study compared BOPTA transport across hepatocytes in livers isolated from normal (Nl) rats and rats with intragastric administration of MCT. BOPTA hepatocyte influx clearance was similar in both groups, while biliary clearance and bile concentrations were much lower in MCT than in Nl livers. BOPTA efflux clearance back to the sinusoids compensated for the low biliary excretion, and hepatocyte concentrations remained similar in both groups. This SOS-associated changes of transporter functions might impact the pharmacokinetics of numerous drugs that use similar transporters to cross hepatocytes.

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A Critical Analysis of Experimental Animal Models of Sinusoidal Obstruction Syndrome

Cited by 7 publications

References 54 publications

Metabolic Toxification of 1,2-Unsaturated Pyrrolizidine Alkaloids Causes Human Hepatic Sinusoidal Obstruction Syndrome: The Update

Metabolic Toxification of 1,2-Unsaturated Pyrrolizidine Alkaloids Causes Human Hepatic Sinusoidal Obstruction Syndrome: The Update

Sinusoidal Obstruction Syndrome Following Myeloablative Therapy and Tranexamic Acid Treatment for Hemorrhage in Two Patients with Neuroblastoma

Monocrotaline Toxicity Alters the Function of Hepatocyte Membrane Transporters in Rats

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