The Redox Imbalance and the Reduction of Contractile Protein Content in Rat Hearts Administered with L-Thyroxine and Doxorubicin

Oxidative stress and disorders in calcium balance play a crucial role in the doxorubicin-induced cardiotoxicity. Moreover, many cardiotoxic targets of doxorubicin are regulated by iodothyronine hormones. The aim of the study was to evaluate effects of tetraiodothyronine (0.2, 2 mg/L) on oxidative stress in the cardiac muscle as well as contractility and cardiomyocyte damage markers in rats receiving doxorubicin (1.5 mg/kg) once a week for ten weeks. Doxorubicin was administered alone (DOX) or together with a lower (0.2T4 + DOX) and higher dose of tetraiodothyronine (2T4 + DOX). Two groups received only tetraiodothyronine (0.2T4, 2T4). Coadministration of tetraiodothyronine and doxorubicin increased the level of lipid peroxidation products and reduced RyR2 level when compared to untreated control and group exposed exclusively to doxorubicin. Insignificant differences in SERCA2 and occasional histological changes were observed. In conclusion, an increase of tetraiodothyronine level may be an additional risk factor of redox imbalance and RyR2 reduction in anthracycline cardiotoxicity

Tirapazamine-Doxorubicin Interaction Referring to Heart Oxidative Stress and Ca2+ Balance Protein Levels

Doxorubicin (DOX) causes long-term cardiomyopathy that is dependent on oxidative stress and contractility disorders. Tirapazamine (TP), an experimental adjuvant drug, passes the same red-ox transformation as DOX. The aim of the study was to evaluate an effect of tirapazamine on oxidative stress, contractile protein level, and cardiomyocyte necrosis in rats administered doxorubicin. Rats were intraperitoneally injected six times once a week with tirapazamine in two doses, 5 (5TP) and 10 mg/kg (10TP), while doxorubicin was administered in dose 1.8 mg/kg (DOX). Subsequent two groups received both drugs simultaneously (5TP+DOX and 10TP+DOX). Tirapazamine reduced heart lipid peroxidation and normalised RyR2 protein level altered by doxorubicin. There were no significant changes in GSH/GSSG ratio, total glutathione, cTnI, AST, and SERCA2 level between DOX and TP+DOX groups. Cardiomyocyte necrosis was observed in groups 10TP and 10TP+DOX

Uncoventional Views on Certain Aspects of Toxin-Induced Metabolic Acidosis

This discussion will highlight the following 9 specific points that related to metabolic acidosis caused by various toxins. The current recommendation suggests that alcohol dehydrogenase inhibitor fomepizole is preferred to ethanol in treatment of methanol and ethylene glycol poisoning, but analysis of the enzyme kinetics indicates that ethanol is a better alternative. In the presence of a modest increase in serum osmolal gap (<30 mOsm/L), the starting dose of ethanol should be far less than the usual recommended dose. One can take advantage of the high vapor pressure of methanol in the treatment of methanol poisoning when hemodialysis is not readily available. Profuse sweating with increased water ingestion can be highly effective in reducing methanol levels. Impaired production of ammonia by the proximal tubule of the kidney plays a major role in the development of metabolic acidosis in pyroglutamic acidosis. Glycine, not oxalate, is the main final end product of ethylene glycol metabolism. Metabolism of ethylene glycol to oxalate, albeit important clinically, represents less than 1% of ethylene glycol disposal. Urine osmolal gap would be useful in the diagnosis of ethylene glycol poisoning, but not in methanol poisoning. Hemodialysis is important in the treatment of methanol poisoning and ethylene glycol poisoning with renal impairment, with or without fomepizole or ethanol treatment. Severe leucocytosis is a highly sensitive indicator of ethylene glycol poisoning. Uncoupling of oxidative phosphorylation by salicylate can explain most of the manifestations of salicylate poisoning

Methanol, formaldehyde, and sodium formate exposure in rat and mouse conceptuses: A potential role of the visceral yolk sac in embryotoxicity

BACKGROUND Methanol (CH 3 OH) is believed to be teratogenic based on rodent studies. The mouse is more sensitive than the rat, but mechanisms of toxicity and identification of teratogenic metabolites are uncertain. METHODS Rat and mouse whole embryo cultures are used to distinguish toxicity of CH 3 OH and its metabolites, formaldehyde (HCHO) and formate (HCOONa), which are produced following transit through the visceral yolk sac (VYS), via addition to culture medium, or by direct embryonic exposure through microinjection into the amnion. RESULTS Embryonic viability, increased dysmorphogenesis, and decreased growth parameters were altered in a dose-dependent fashion for each compound. Mouse embryos were more sensitive than rat, as indicated by significant decreases in viability at comparable, lower concentrations. HCHO produced dysmorphogenesis and caused embryolethality at nearly 1000-fold lower concentrations (0.004 mg/ml) than seen with either CH 3 OH or HCOONa. All agents produced incomplete axial rotation and delayed neural tube closure in mice, but only CH 3 OH elicited similar effects in the rat. Increased growth retardation, blood pooling in the head and VYS, enlarged pericardium, accumulation of necrotic matter in the amnion, and hypoplastic prosencephalon were observed in both species with all compounds. Microinjection of compounds into the amnion produced higher mortality in mouse and rat, compared to equimolar amounts added to the culture medium. CH 3 OH did not prevent neural tube closure in the rat when microinjected. CONCLUSIONS HCHO is the most embryotoxic CH 3 OH metabolite and elicits the entire spectrum of lesions produced by CH 3 OH. The VYS serves a general protective role against toxicity and inherent differences in the embryonic metabolism of CH 3 OH may determine species sensitivity. Birth Defects Research (Part A), 2004. © 2004 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/35296/1/20094_ftp.pd