Toxicology and applied pharmacology
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Toxicol. Appl. Pharmacol. · May 2018
Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6) are associated with long term tramadol treatment-induced oxidative damage and hepatotoxicity.
Our objective was to figure out whether CYP2D6 gene polymorphisms may account for long term tramadol-induced oxidative stress and hepatotoxicity in 60 patients receiving chronic tramadol treatment in Neurology and Rheumatology Outpatients Clinic, Zagazig University Hospitals, Egypt. As expected, CYP2D6*1 allele (wild type) frequency was significantly greater than CYP2D6*DUP, CYP2D6*4 and CYP2D6*10 alleles in both chronically tramadol-treated and control groups. In tramadol-treated patients, CYP2D6*DUP allele carriers followed by those carrying CYP2D6*1, displayed higher levels of urinary tramadol major active metabolite, O-desmethyltramadol (M1) and serum lipid peroxidation along with lower levels of total antioxidants than those carrying other impaired function alleles (CYP2D6*4&*10), suggesting oxidative stress. ⋯ Moreover, we reported that in 42 patients with allele *1, tramadol caused mild to moderate hepatotoxicity (grades: 1-2) within 13-16 months while in 7 patients with duplicated allele (*DUP), tramadol caused moderate to severe hepatotoxicity (grades: 2-3) within 10-11 months (moderately longer period but shorter than that observed in allele *1), implying that exposure to tramadol for longer time in extensive and ultra-rapid metabolizers may contribute to hepatotoxicity development. Overall, our results suggest that CYP2D6 gene polymorphisms, particularly enhanced or normal function of CYP2D6, may increase the vulnerability to long term tramadol-induced hepatotoxicity through the enhancement of accumulation of tramadol bioactive metabolite (M1) and hence oxidative stress. Therefore, tramadol doses should be adjusted according to patient's CYP2D6 genotyping analysis to avoid hepatotoxicity.
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Toxicol. Appl. Pharmacol. · Sep 2017
The effect of fibroblast growth factor 15 deficiency on the development of high fat diet induced non-alcoholic steatohepatitis.
Non-alcoholic steatohepatitis (NASH) is a form of non-alcoholic fatty liver disease (NAFLD) characterized by steatosis, inflammation, and fibrosis often associated with metabolic syndrome. Fibroblast growth factor 15 (FGF15), an endocrine factor mainly produced in the distal part of small intestine, has emerged to be a critical factor in regulating bile acid homeostasis, energy metabolism, and liver regeneration. We hypothesized that FGF15 alters the development of each of the listed features of NASH. ⋯ Whereas FGF15 deficiency had no effect on the severity of liver steatosis or inflammation, it was associated with decreased liver fibrosis. Furthermore, FGF15 deficiency resulted in abnormal bile acid homeostasis, increased insulin resistance, increased HFD-induced serum triglycerides, decreased inductions of hepatic cholesterol content by HFD, and altered gene expression of lipid metabolic enzymes. These data suggest that FGF15 improves lipid homeostasis and reduces bile acid synthesis, but promotes fibrosis during the development of NASH.
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Toxicol. Appl. Pharmacol. · Aug 2017
An impedance-based approach using human iPSC-derived cardiomyocytes significantly improves in vitro prediction of in vivo cardiotox liabilities.
Current in vitro approaches to cardiac safety testing typically focus on mechanistic ion channel testing to predict in vivo proarrhythmic potential. Outside of the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative, structural and functional cardiotoxicity related to chronic dosing effects are of great concern as these effects can impact compound attrition. Development and implementation of an in vitro cardiotoxicity screening platform that effectively identifies these liabilities early in the discovery process should reduce costly attrition and decrease preclinical development time. ⋯ These assays correctly predicted in vivo cardiotox findings for 81% of the compounds tested and did not identify false positives. In addition, internal or literature Cmax values from in vivo studies correlated within 4 fold of the in vitro observations. The work presented here demonstrates the predictive power of impedance platforms with hIPSC-CMs and provides a means toward accelerating lead candidate selection by assessing preclinical cardiac safety earlier in the drug discovery process.
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Toxicol. Appl. Pharmacol. · Sep 2016
Activation of angiotensin-converting enzyme 2 (ACE2) attenuates allergic airway inflammation in rat asthma model.
Angiotensin-I converting enzyme (ACE) is positively correlated to asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and is highly expressed in lungs. ACE2, the counteracting enzyme of ACE, was proven to be protective in pulmonary, cardiovascular diseases. In the present study we checked the effect of ACE2 activation in animal model of asthma. ⋯ Intraalveolar interstitial thickening, inflammatory cell infiltration, interstitial fibrosis, oxidative stress and right ventricular hypertrophy in asthma control animals were also reversed by DIZE treatment. Activation of ACE2 by DIZE conferred protection against asthma as evident from biochemical, functional, histological and molecular parameters. To the best of our knowledge, we report for the first time that activation of ACE2 by DIZE prevents asthma progression by altering AKT, p38, NF-κB and other inflammatory markers.
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Toxicol. Appl. Pharmacol. · Nov 2015
Morphine preconditioning confers cardioprotection in doxorubicin-induced failing rat hearts via ERK/GSK-3β pathway independent of PI3K/Akt.
Preconditioning against myocardial ischemia-reperfusion (I/R) injury can be suppressed in some pathological conditions. This study was designed to investigate whether morphine preconditioning (MPC) exerts cardioprotection in doxorubicin (DOX)-induced heart failure in rats and the mechanisms involved. Phosphatidylinositol-3 kinase/protein kinase B (PI3K/Akt), extracellular signal-regulated kinase (ERK) and glycogen synthase kinase (GSK)-3β pathways were examined. ⋯ IPC did not elevate the expression of p-ERK, p-Akt and p-GSK-3β in failing rat hearts. We conclude that MPC is cardioprotective in rats with DOX-induced heart failure while IPC is not. The effect of MPC appears to be mediated via the ERK/GSK-3β pathway independent of PI3K/Akt.