Journal of Applied Toxicology

Tyrosine kinase inhibitors (TKI)-induced cardiac toxicity in cancer patients was not well predicted by preclinical studies, owing to the lack of a comprehensive TKI mechanism of action and appropriate cardiac functional evaluation. To help close the gaps, additional preclinical testing is proposed, including: precise determination of the mechanism of action, cardiomyocyte cultures for screening potentially cardiotoxic drugs, functional assessments using isolated perfused heart methodology or echocardiography, and assessment of both safety and efficacy in animal models of disease.

Most studies on the melatonin (MLT) hypothesis in rats have reported partial inhibition of MLT secretion under long term exposure to weak ELF magnetic fields (MF). Recent data on magnetoreception and on cancer promotion by circadian disruption encourage to go back to the MLT hypothesis, with applying it the association between ELF MF and childhood leukemia, and with envisaging possible involvement of the magnetic sense.

To clarify the general toxicity of acrylamide in the juvenile rats, acrylamide was administered to F344 rats after birth for 12 weeks. Reduction of body weight was noted in 20 and 40 ppm females. Acrylamide-induced histopathological changes were limited to degeneration and necrosis of the seminiferous epithelium in the testes and desquamated epithelium in the epididymides in 40 ppm males. Taken together with previous reports, juvenile rats are not necessarily more susceptible to acrylamide-induced toxicity as compared with young adults.

Naphthenic acids (NAs) are believed to be the major toxic component of oil sands process water (OSPW). We evaluated whether commercial NAs are an adequate model to study OSPW toxicity in complex organisms. We compared the effects of commercial NAs preparation and the organic fraction of OSPW by measuring the pro-inflammatory gene expression and macrophage phagocytosis, and found that commercial NAs and OSPW induce different biological effects in mice.

In this study, primary cultures of chicken tibial growth plate chondrocytes were treated with T-2 toxin in the absence and presence of N-acetyl-cysteine (NAC) to investigate the effects of NAC on T-2 toxin toxicity. Our results showed that T-2 toxin-induced cytotoxicity was reversed, in part, by antioxidant NAC (P < 0.05), suggesting that T-2 toxin inhibits the proliferation and differentiation of GPCs in vitro by altering cellular homeostasis and NAC can protect GPCs against T-2 toxin cytotoxicity.

The aim of the present study was to evaluate the apoptotic effects of piceatannol and myricetin, alone or in combination, in HL-60 (leukemia) and HepG2 (hepatoma) cells. Both polyphenols induced apoptotic cell death synergistically in HL-60 cells. However, the percentage of apoptotic HepG2 cells was only significant after piceatannol treatment and in combined treatment was even lower. Our results also indicate that apoptosis induced by piceatannol and myricetin occurs through an ROS-independent cell death pathway.

The effects of six fruits-banana, guava, mangosteen, pineapple, ripe mango, and ripe papaya-on murine CYP1A1, CYP1A2, CYP2E1, and CYP3A11 activities were investigated. Pineapple juice showed the strongest inhibitory effect against P450s in vitro, followed by mangosteen, guava, ripe mango, ripe papaya, and banana. In vivo, the pineapple juice raised ethoxyresorufin O-deethylase, aniline hydroxylase, and erythromycin N-demethylase activities, corresponded to the expression of CYP1A1, CYP2E1, and CYP3A11 mRNAs. These observations supported that these fruits were a feasible cause of food-drug interaction.

Hepatic ethoxyresorufin O-deethylase (EROD), methoxyresorufin O-demethylase (MROD), pentoxyresorufin O-dealkylase (PROD) and benzyloxyresorufin O-dealkylase (BROD) enzyme activities were determined in ICR, C57BL/6, and DBA/2 mice; Sprague Dawley and Wistar rats; and Dunkin Hartley guinea pigs using β-naphthoflavone, dexamethasone and phenobarbital as inducers. Maximal induction of EROD, MROD, PROD and BROD activities were found in different strains with different inducers. These observations suggested that the choice of experimental animal strain, species and inducer is of critical importance for studies of drug metabolism and interaction.

PF-04254644, a HGFR/c-MET inhibitor with off-target PDE inhibition, caused cardiomyopathy and sustained increased in heart rate in rats. Investigative studies identified PDEs inhibition, activation of c-AMP signaling, followed by intracellular calcium and oxidative stress signaling pathways as potential mechanisms of cardiac changes. Our studies substantiate the off-target mechanisms involved in the toxic effects of PF-04254644.