Inhibitory Effect of Cyclosporin A Peptide on Rat Hepatocytes Proliferation Induced by Mitogens

Rodríguez-Henche, Nieves; Domingo, Alberto; Fueyo, Jesús; Menor, César; Zueco, José Antonio; Prieto, Juan Carlos; Guijarro, Luis

doi:10.1016/s0196-9781(97)00466-x

Cited by 2 publications

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“…19 In previous studies, an inhibitory posttranslational effect of FK506 on insulin receptor expression was noted in cultured bovine adrenal gland cells. 20 However, similar discrepancies in the effects of FK506 on hepatocyte proliferation have been observed when comparing in vitro 21 or in vivo 1 models. In the same way, treatment of cultured hepatocytes with CsA inhibits thymidine incorporation into DNA 21 and increases apoptosis, 22 whereas the opposite occurs after the in vivo administration of CsA before PH.…”

Section: Discussionmentioning

confidence: 64%

“…20 However, similar discrepancies in the effects of FK506 on hepatocyte proliferation have been observed when comparing in vitro 21 or in vivo 1 models. In the same way, treatment of cultured hepatocytes with CsA inhibits thymidine incorporation into DNA 21 and increases apoptosis, 22 whereas the opposite occurs after the in vivo administration of CsA before PH. 23 The changes in insulin receptor expression after FK506 treatment observed here cannot be attributed to a diabetic state because neither drug pretreatment nor PH provoked a dramatic change in circulating glucose levels.…”

Section: Discussionmentioning

confidence: 64%

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Pretreatment with FK506 up-regulates insulin receptors in regenerating rat liver

et al. 2002

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This report examines the effect of FK506 pretreatment on liver insulin receptor expression in partially (70%) hepatectomized rats. FK506 pretreatment led to an increased insulin receptor number 24 hours after hepatectomy, detected by means of insulin binding and crosslinking procedures. This increase was related to enhanced insulin receptor expression determined by in vitro mRNA translation and Western blot techniques. We also tested the functionality of the expressed insulin receptors by [ 3 H] thymidine incorporation into DNA in insulin-stimulated hepatocytes. The results show that FK506 pretreatment elicits an increase in the amount of insulin receptor ␣-subunits as measured by Western blot. Maximum ␣-subunit expression recorded 24 hours after surgery was preceded by increased insulin receptor mRNA levels, which were detected 6 hours after hepatectomy. Moreover, in FK506 -pretreated rat hepatocytes, obtained from remnant livers 24 hours after partial hepatectomy (PH), the increase in insulin receptor number was associated with improved sensitivity to the hormone. However, in both experimental groups (FK506-pretreated and nonpretreated rats), the sensitivity of hepatocytes toward epidermal growth factor (EGF) showed no significant change, which suggests a specific effect of FK506 on insulin receptor expression. In conclusion, our findings suggest that FK506 pretreatment induces insulin receptor expression in regenerating rat liver and promotes liver regeneration in hepatectomized rats. (HEPATOLOGY 2002;36:555-561.) P retreatment with immunosuppressive drugs, such as FK506 and cyclosporin A (CsA), increases the liver regenerative response after partial hepatectomy (PH) in rats. 1 Several research efforts have tried to determine the factors involved in the proliferative response associated with drug treatment. FK506 or CsA could modulate the liver response by (1) increasing the expression of local mitogens such as hepatocyte growth factor 2 or insulin-like growth factor I 3 ; (2) decreasing the production of inhibitory cytokines such as transforming growth factor ␤ 1 2 or interleukin 2 4 ; (3) inhibiting natural killer activity 4 ; or (4) predisposing the liver to regenerative signals. This last hypothesis has been suggested but not shown. Insulin is considered a secondary mitogen that enhances liver sensitivity to mitogens during its regeneration. 5 Administering insulin to 70% PH rats increases [ 3 H] thymidine labeling of DNA in hepatic parenchyma cells. 6 Insulin induces a specific peak in [ 3 H] thymidine incorporation 24 hours after PH, which is not observed in insulin-untreated or glucagon-treated animals. 6 This 24-hour period after PH also coincides with maximal effects of FK506 1 or CsA 2 on the liver regenerative response. Moreover, the role of insulin in liver regeneration is supported by its blunting of the immediate-early gene response after PH in diabetic animals. 7 In a very recent study performed in 70% PH/50% pancreatectomized rats, it was shown that liver mass recovery in these animals was del...

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 64%

Pretreatment with FK506 up-regulates insulin receptors in regenerating rat liver

et al. 2002

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Azathioprine Acts upon Rat Hepatocyte Mitochondria and Stress-Activated Protein Kinases Leading to Necrosis: Protective Role of N-Acetyl-L-cysteine

Menor¹,

Fernández‐Moreno²,

Fueyo³

et al. 2004

J Pharmacol Exp Ther

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Azathioprine is an immunosuppressant drug widely used. Our purpose was to 1) determine whether its associated hepatotoxicity could be attributable to the induction of a necrotic or apoptotic effect in hepatocytes, and 2) elucidate the mechanism involved. To evaluate cellular responses to azathioprine, we used primary culture of isolated rat hepatocytes. Cell metabolic activity, reduced glutathione, cell proliferation, and lactate dehydrogenase release were assessed. Mitochondria were isolated from rat livers, and swelling and oxygen consumption were measured. Mitogen-activated protein kinase pathways and proteins implicated in cell death were analyzed. Azathioprine decreased the viability of hepatocytes and induced the following events: intracellular reduced glutathione (GSH) depletion, metabolic activity reduction, and lactate dehydrogenase release. However, the cell death was not accompanied by DNA laddering, procaspase-3 cleavage, and cytochrome c release.The negative effects of azathioprine on the viability of hepatocytes were prevented by cotreatment with N-acetyl-L-cysteine. In contrast, 6-mercaptopurine showed no effects on GSH content and metabolic activity. Azathioprine effect on hepatocytes was associated with swelling and increased oxygen consumption of intact isolated rat liver mitochondria. Both effects were cyclosporine A-sensitive, suggesting an involvement of the mitochondrial permeability transition pore in the response to azathioprine. In addition, the drug's effects on hepatocyte viability were partially abrogated by c-Jun N-terminal kinase and p38 kinase inhibitors. In conclusion, our findings suggest that azathioprine effects correlate to mitochondrial dysfunction and activation of stress-activated protein kinase pathways leading to necrotic cell death. These negative effects of the drug could be prevented by coincubation with N-acetyl-L-cysteine.

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Inhibitory Effect of Cyclosporin A Peptide on Rat Hepatocytes Proliferation Induced by Mitogens

Cited by 2 publications

References 42 publications

Pretreatment with FK506 up-regulates insulin receptors in regenerating rat liver

Pretreatment with FK506 up-regulates insulin receptors in regenerating rat liver

Azathioprine Acts upon Rat Hepatocyte Mitochondria and Stress-Activated Protein Kinases Leading to Necrosis: Protective Role of N-Acetyl-L-cysteine

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