Second, adaptation may reflect the dampening of the hazard induced by drugs. A number of possibilities can be considered including decreased exposure to the toxic moiety, enhanced phase 2 or 3 defense (e.g., GSH, antioxidant enzymes, nontoxic metabolism, or MRP2 and other adenosine triphosphate [ATP] dependent export pump expression), unfolded protein responses in the ER or mitochondria, mitochondrial adaptive responses such as mitophagy or biogenesis, and regeneration with proliferation of resistant hepatocytes. Further adding to the complexity of susceptibly to IDILI is the modulation of these adaptive responses by genetic variations and environmental factors. In conclusion, selleck chemicals the “rule-of-two”
seems to offer some added value in identifying the potential for IDILI. Aside from its application in candidate selection in drug development
by industry, it may be worth exploring as a component of future causality assessment tools especially when weighing the contribution of multiple concomitant medications. The strong relationship between KPT-330 research buy dose, lipophilicity, and IDILI underscores the key role of exposure of the liver to a threshold level of hazardous chemicals. “
“Hepatocellular carcinoma (HCC) is a common cause of cancer-related death. Sorafenib prolongs survival of patients with advanced disease and is approved for the systemic treatment of unresectable HCC. It possesses antiangiogenic and antiproliferative properties by way of inhibition of the receptor tyrosine kinases vascular endothelial growth factor receptor 2 (VEGFR-2)
and platelet-derived growth factor receptor-beta 1/2 (PDGFR-β) and the kinase RAF. Sorafenib represents a candidate compound for adjuvant therapy in HCC patients. The aim of our study was to investigate whether sorafenib affects liver regeneration. C57BL6 mice received sorafenib orally at 30 mg/kg/day or its vehicle either for 14 days until the day before hepatectomy or starting the day after surgery or both. Animals were sacrificed 24, 72, and 120 hours after hepatectomy. Liver regeneration was click here calculated as a percent of initial liver weight. Bromodeoxyuridine (BrdU) incorporation and phospho-extracellular signal-regulated kinase (pERK1/2) were determined by immunohistochemistry on liver sections. VEGF-A, PDGF-BB, and hepatocyte growth factor (HGF) levels were measured in liver tissue homogenates. Histological analysis of scar tissue was performed. Treatment stopped 1 day before surgery had no impact on liver regeneration. Continuous sorafenib treatment and treatment started 1 day after surgery had statistically significant effects on liver regeneration at 120 hours compared to vehicle-treated control animals (72% ± 12 versus control 88% ± 15 and 70% ± 13 versus control 86% ± 5 at 120 hours, both P ≤ 0.02). BrdU incorporation showed decreased numbers of positive nuclei in both groups receiving sorafenib after surgery. Phospho-ERK levels were reduced in sorafenib-treated animals.