Animal models of hepatotoxicity

Bhakuni, Ganesh Singh; Bedi, Onkar; Bariwal, Jitender; Deshmukh, Rahul; Kumar, Puneet

doi:10.1007/s00011-015-0883-0

Cited by 44 publications

(35 citation statements)

References 79 publications

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“…The evaluation of hepatotoxicity of pharmaceutical substances is one major aspect of drug development. For in vivo hepatotoxicity testing, animal models, especially rats and mice, are currently the method of choice [ 1 , 2 ]. However, the use of such models is controversial as they often do not accurately represent the human metabolism due to differences in pharmacokinetics, pharmacodynamics, and species-specific genetic variations [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Microscale 3D Liver Bioreactor for In Vitro Hepatotoxicity Testing under Perfusion Conditions

et al. 2018

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The accurate prediction of hepatotoxicity demands validated human in vitro models that can close the gap between preclinical animal studies and clinical trials. In this study we investigated the response of primary human liver cells to toxic drug exposure in a perfused microscale 3D liver bioreactor. The cellularized bioreactors were treated with 5, 10, or 30 mM acetaminophen (APAP) used as a reference substance. Lactate production significantly decreased upon treatment with 30 mM APAP (p < 0.05) and ammonia release significantly increased in bioreactors treated with 10 or 30 mM APAP (p < 0.0001), indicating APAP-induced dose-dependent toxicity. The release of prostaglandin E2 showed a significant increase at 30 mM APAP (p < 0.05), suggesting an inflammatory reaction towards enhanced cellular stress. The expression of genes involved in drug metabolism, antioxidant reactions, urea synthesis, and apoptosis was differentially influenced by APAP exposure. Histological examinations revealed that primary human liver cells in untreated control bioreactors were reorganized in tissue-like cell aggregates. These aggregates were partly disintegrated upon APAP treatment, lacking expression of hepatocyte-specific proteins and transporters. In conclusion, our results validate the suitability of the microscale 3D liver bioreactor to detect hepatotoxic effects of drugs in vitro under perfusion conditions.

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Section: Introductionmentioning

confidence: 99%

Microscale 3D Liver Bioreactor for In Vitro Hepatotoxicity Testing under Perfusion Conditions

et al. 2018

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“…Rodent and human physiology are very similar, and various mouse models have been used widely in the study of liver anatomy and function in healthy and diseased forms, noting that animal models known so far in the study of human liver diseases manage to mimic specific features of the human disease but not all . Given the wide genetic variation existing between human populations alongside the multiple limitations in human study (eg, weak control for standardized investigations), studying a complex human trait or disease requires a highly genetically diverse mouse population rather than a single mouse model.…”

Section: Introductionmentioning

confidence: 99%

Mapping novel genetic loci associated with female liver weight variations using Collaborative Cross mice

Atamni

Botzman

Mott

et al. 2018

Anim Models and Exp Med

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Background Liver weight is a complex trait, controlled by polygenic factors and differs within populations. Dissecting the genetic architecture underlying these variations will facilitate the search for key role candidate genes involved directly in the hepatomegaly process and indirectly involved in related diseases etiology. Methods Liver weight of 506 mice generated from 39 different Collaborative Cross ( CC ) lines with both sexes at age 20 weeks old was determined using an electronic balance. Genomic DNA of the CC lines was genotyped with high‐density single nucleotide polymorphic markers. Results Statistical analysis revealed a significant ( P < 0.05) variation of liver weight between the CC lines, with broad sense heritability ( H 2 ) of 0.32 and genetic coefficient of variation ( CV G ) of 0.28. Subsequently, quantitative trait locus ( QTL ) mapping was performed, and results showed a significant QTL only for females on chromosome 8 at genomic interval 88.61‐93.38 Mb (4.77 Mb). Three suggestive QTL were mapped at chromosomes 4, 12 and 13. The four QTL were designated as LWL 1‐ LWL 4 referring to liver weight loci 1‐4 on chromosomes 8, 4, 12 and 13, respectively. Conclusion To our knowledge, this report presents, for the first time, the utilization of the CC for mapping QTL associated with baseline liver weight in mice. Our findings demonstrate that liver weight is a complex trait controlled by multiple genetic factors that differ significantly between sexes.

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“…The existence of a systemic circulatory disorder in liver cirrhosis was described more than 60 years ago (Kowalski and Abelmann 1953), nevertheless the underlying mechanisms involved in pathogenesis are still poorly understood and treatment of cirrhotic cardiomyopathy is limited, partially due to the lack of satisfactory animal models. There are many experimental models to induce hepatic fibrosis (Bhakuni et al 2016). However, none of them systematically evaluates similarities and differences between animal models of cirrhotic cardiomyopathy and clinical picture of the disease.…”

Section: Discussionmentioning

confidence: 99%

Expression of classical mediators in hearts of rats with hepatic dysfunction

Jarkovská

Bludovská

Mistrová

et al. 2017

Can. J. Physiol. Pharmacol.

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Liver cirrhosis is associated with impairment of cardiovascular function including alterations of the heart innervation, humoral and nervous dysregulation, changes in systemic circulation and electrophysiological abnormalities. Choline acetyltransferase (ChAT), enzyme forming acetylcholine, tyrosine hydroxylase (TH), and dopamine-β-hydroxylase (DBH), enzymes participating in noradrenaline synthesis, are responsible for the production of classical neurotransmitters, and atrial natriuretic peptide (ANP) is produced by cardiomyocytes. The aim of this study was to evaluate the influence of experimentally induced hepatic dysfunction on the expression of proANP, ChAT, TH, and DBH in the heart. Hepatic dysfunction was induced by application of thioacetamide (TAA) or by ligation of bile duct. Biochemical parameters of hepatic injury and levels of peroxidation in the liver and heart were measured. Liver enzymes measured in the plasma were significantly elevated. Cardiac level of peroxidation was increased in operated but not TAA group animals. In the left atrium of operated rats, the expression of TH and DBH was lower, while expression of ChAT remained unchanged. In TAA group, no significant differences in the expression of the genes compared to controls were observed. Liver injury induced by ligation leads to an imbalance in the intracardiac innervation, which might impair nervous control of the heart.

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Animal models of hepatotoxicity

Abstract: In this review, we revealed various animal models with their merits and demerits. Our main focus is to explore all new and traditional animal models under broad classification like non-invasive, invasive and genetic models which directly or indirectly produce hepatotoxicity.

Cited by 44 publications

References 79 publications

Microscale 3D Liver Bioreactor for In Vitro Hepatotoxicity Testing under Perfusion Conditions

Microscale 3D Liver Bioreactor for In Vitro Hepatotoxicity Testing under Perfusion Conditions

Mapping novel genetic loci associated with female liver weight variations using Collaborative Cross mice

Expression of classical mediators in hearts of rats with hepatic dysfunction

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