1,4‐Bis[2‐(3,5‐dichloropyridyloxy)]benzene induces substantial hyperplasia in fibrotic mouse liver

Bugyik, Edina; Dezső, Katalin; Turányi, Eszter; Szurián, Kinga; Paku, Sándor; Nagy, Péter

doi:10.1111/j.1365-2613.2011.00803.x

Cited by 4 publications

(4 citation statements)

References 23 publications

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“…: 347580; BD Biosciences, Franklin Lakes, NJ; dil. : 1:20) as described before [ 23 ]. 5000 hepatocytes and 500 ductular cells were counted, the percentage of BrdU-positive cells was given as a result.…”

Section: Methodsmentioning

confidence: 99%

Ductular reaction correlates with fibrogenesis but does not contribute to liver regeneration in experimental fibrosis models

et al. 2017

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Background and aimsDuctular reaction is a standard component of fibrotic liver tissue but its function is largely unknown. It is supposed to interact with the matrix producing myofibroblasts and compensate the declining regenerative capacity of hepatocytes. The relationship between the extent of fibrosis—ductular reaction, proliferative activity of hepatocytes and ductular reaction were studied sequentially in experimental hepatic fibrosis models.MethodsLiver fibrosis/cirrhosis was induced in wild type and TGFβ overproducing transgenic mice by carbon tetrachloride and thioacetamide administration. The effect of thioacetamide was modulated by treatment with imatinib and erlotinib. The extent of ductular reaction and fibrosis was measured by morphometry following cytokeratin 19 immunofluorescent labeling and Picro Sirius staining respectively. The proliferative activity of hepatocytes and ductular reaction was evaluated by BrdU incorporation. The temporal distribution of the parameters was followed and compared within and between different experimental groups.ResultsThere was a strong significant correlation between the extent of fibrosis and ductular reaction in each experimental group. Although imatinib and erlotinib temporarily decreased fibrosis this effect later disappeared. We could not observe negative correlation between the proliferation of hepatocytes and ductular reaction in any of the investigated models.ConclusionsThe stringent connection between ductular reaction and fibrosis, which cannot be influenced by any of our treatment regimens, suggests that there is a close mutual interaction between them instead of a unidirectional causal relationship. Our results confirm a close connection between DR and fibrogenesis. However, since the two parameters changed together we could not establish a causal relationship and were unable to reveal which was the primary event. The lack of inverse correlation between the proliferation of hepatocytes and ductular reaction questions that ductular reaction can compensate for the failing regenerative activity of hepatocytes. No evidences support the persistent antifibrotic property of imatinib or erlotinib.

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Section: Methodsmentioning

confidence: 99%

Ductular reaction correlates with fibrogenesis but does not contribute to liver regeneration in experimental fibrosis models

et al. 2017

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“…This mitogenic effect of TCPOBOP in liver cells was recently shown to be a possible alternative for the rescue of regenerative response in cirrhotic livers (Bugyik et al, 2012). However, attention should be given before using Nr1i3 ligands for any therapeutic purposes since we showed here that caffeine, a substance consumed worldwide, potentiated some effects of the Nr1i3 ligand in mice.…”

Section: Discussionmentioning

confidence: 57%

“…We previously showed that a single administration of TCPOBOP to mice induced hepatomegaly doubling liver weight at 72 h (Fukumasu et al, 2010). This effect mainly occurred due to increased cell proliferation (hyperplasia) over hepatocyte hypertrophy after TCPOBOP administration (Fukumasu et al, 2010;Bugyik et al, 2012). In addition, TCPOBOP transiently disrupted intercellular communication by GAP junctions in mouse liver (Fukumasu et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Caffeine increases Nr1i3 expression and potentiates the effects of its ligand, TCPOBOP, in mice liver

Fukumasu

Rochetti

Latorre

et al. 2015

Braz. J. Pharm. Sci.

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Caffeine is one of the world's most consumed substances. It is present in coffee, green tea and guarana, among others. The xenobiotic-sensing nuclear receptor subfamily 1, group I, member 3 (Nr1i3), also known as the Constitutive Androstane Receptor (Car) is a key regulator of drug metabolism and excretion. No consistent description of caffeine effects on this receptor has been described. Thus, to unravel the effects of caffeine on this receptor, we performed experiments in mice. First, C57Bl/6 mice that were treated daily with caffeine (50 mg/kg) for 15 days presented a slight but significant increase in Nr1i3 and Cyp2b10 gene expression. A second experiment was then performed to verify the effects of caffeine on TCPOBOP (1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene, 3,3′,5,5′-tetrachloro-1,4-bis(pyridyloxy) benzene), the most potent agonist known for mice Nr1i3. Interestingly, caffeine potentiated TCPOBOP pleiotropic effects in mice liver, such as hepatomegaly, hepatotoxicity, hepatocyte proliferation and loss of cell-to-cell communication through gap junctions. In addition, caffeine plus TCPOBOP treatment increased liver gene expression of Nr1i3 and Cyp2b10 comparing with only caffeine or TCPOBOP treatments. Together, these results indicate that caffeine increases the expression of Nr1i3 in mice liver, although at this point it is not possible to determine if Nr1i3 directly or indirectly mediates this effect.Uniterms: Caffeine/effects/experimental study. Androstane constitutive receptor/caffeine effects. 1,4-bis-[2-(3,5-dichloropyridiloxy)]benzeno,3,3′,5,5-tetracloro-1,4-bis(pyridiloxy)benzene/caffeine effects. Cytochrome p450.A cafeína é uma das substâncias mais consumidas mundialmente, estando presente no café, chá-verde e guaraná, entre outros. O receptor sensor de xenobióticos Receptor Nuclear subfamília 1, grupo I, membro 3 (Nr1i3, mais conhecido como Androstano Consititutivo -Car) é um regulador chave da biotransformação e excreção de substâncias e nenhuma descrição consistente dos efeitos da cafeína sobre este receptor foi feita. Então, para avaliar os efeitos da cafeína sobre este receptor, realizamos experimentos em camundongos. Primeiramente, camundongos C57/Bl/6 foram tratados diariamente com cafeína (50 mg/kg) por 15 dias e apresentaram um leve, mas significativo, aumento na expressão do Car e do seu gene alvo Cyp2b10. Assim, um segundo experimento foi realizado para verificar os efeitos da cafeína sobre o TCPOBOP (1,4-bis-[2-(3,5-dicloropiridiloxi)]benzeno,3,3′,5,5′-tetracloro-1,4-bis(piridiloxi)benzeno), o mais potente agonista do Nr1i3 de camundongos conhecido. Interessantemente, a cafeína potencializou os efeitos pleiotrópicos do TCPOBOP no fígado dos camundongos, como hepatomegalia, hepatotoxicidade, proliferação celular e perda da comunicação intercelular por junções do tipo gap. Os camundongos tratados com cafeína e TCPOBOP apresentaram maior expressão gênica de Nr1i3 e Cyp2b10, quando comparados aos camundongos tratados apenas com cafeína ou TCPOBOP. Juntos, nossos resultados indicam que a ...

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“…The enzymatic activity of CYP3A was also unchanged in CCl 4 ‐administered mice (Figure 3), which was consistent with the results of Cyp3a11 mRNA expression. The mRNA expression of Cyp3a11 and Cyp2b10 varied in mice administered with a high dose of CCl 4 for a few weeks in previous reports (Bugyik et al., 2012; Shan et al., 2008; Yuan et al., 2022). Hepatitis developed using our method did not affect basal CYP expression and function.…”

Section: Discussionmentioning

confidence: 79%

Attenuation of phenobarbital‐induced cytochrome P450 expression in carbon tetrachloride‐induced hepatitis in mice models

Fujino

Kuzu

Kubo

et al. 2023

Biopharm & Drug Disp

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Certain pathological conditions, such as inflammation, are known to affect basal cytochrome P450 (CYP) expression by modulating transcriptional regulation, and the pharmacokinetics of drugs can vary among patients. However, changes in drug‐induced CYP expression under pathological conditions have not been elucidated in detail. Here, we investigated the effects of hepatic inflammation and injury on phenobarbital‐induced expression of CYP isoforms in mice. Phenobarbital was administered once as a CYP inducer in the carbon tetrachloride‐induced hepatitis model mice. The mRNA expression levels of Cyp3a11 and Cyp2b10 in the liver and small intestine were measured using reverse transcription polymerase chain reaction. The enzymatic activity of CYP3A in liver S9 was evaluated using midazolam as the substrate. Phenobarbital increased the mRNA expression of Cyp3a11 and Cyp2b10 in the liver of healthy mice, but not in the small intestine. Increased mRNA expression of hepatic Cyp3a11 and Cyp2b10 by phenobarbital was significantly suppressed in the hepatitis model mice. Hepatitis also suppressed the increased CYP3A enzymatic activity induced by phenobarbital in liver S9, consistent with the results of Cyp3a11 mRNA expression. These results suggest that the inducibility of CYP by phenobarbital may vary in patients with hepatitis, indicating that pharmacokinetic drug–drug interactions can be altered under certain pathological conditions.

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1,4‐Bis[2‐(3,5‐dichloropyridyloxy)]benzene induces substantial hyperplasia in fibrotic mouse liver

Cited by 4 publications

References 23 publications

Ductular reaction correlates with fibrogenesis but does not contribute to liver regeneration in experimental fibrosis models

Ductular reaction correlates with fibrogenesis but does not contribute to liver regeneration in experimental fibrosis models

Caffeine increases Nr1i3 expression and potentiates the effects of its ligand, TCPOBOP, in mice liver

Attenuation of phenobarbital‐induced cytochrome P450 expression in carbon tetrachloride‐induced hepatitis in mice models

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