Compared with that in the control cells, the initial rapid uptake of ascorbate in cobalt(II)-exposed cells has stopped 2–4 h after the addition of the cobalt to the cell culture medium. Then, within the next 16–18 h, the cellular [14C] ascorbate decreased gradually to barely detectable levels. This time course could be the result of a relatively slow interaction of the metals (or metal complexes) with critical target molecules (ligands) in the medium and/or cells, including ascorbic acid. Exposure

of cells to cobalt(II) causes activation of the HIF-1 transcription factor and up-regulates many of the hypoxia-inducible genes (Yuan et al., 2003). However, the exact mechanism of HIF-1 activation by cobalt (and also other metals) is not known. Very selleck chemical recently it has been shown that HIF-1alpha stabilization in human lung

epithelial cells occurred following exposure to various metal ions, including those that cannot substitute for iron in the hydroxylases. In each case addition of the reducing agent (ascorbic acid) abolished HIF-1alpha protein stabilization. To better understand JNK signaling inhibitors the role of iron oxidation in hydroxylase inhibition and to define the role of ascorbic acid in the enzyme recovery, applied molecular modeling techniques were adopted. The results indicate that the energy required for iron substitution by divalent metal ions in the enzyme is high and unlikely to be achieved in a biological system (Kaczmarek et al., 2009). As described above, cobalt is a

potent inducer of oxidative stress causing free radical generation, which in turn induce DNA damage, inhibit DNA repair mechanisms and the exchange of DNA between sister-chromatids and aneuploidy (Galanis et al., 2009). The toxicity of cobalt is relatively low compared to many other metals (Gal et al., 2008). Its toxic effect in higher concentrations affects mainly the lungs, leading to asthma, pneumonia and MRIP wheezing. Overdosing of cobalt (>5 mg/day) may lead to abnormal thyroid functions, polycythemia and overproduction of red blood cells (erythropoiesis), with increased production of the hormone erythropoietin. There is also a risk of pulmonary edema, peripheral vascular thrombosis, optic nerve atrophy. Intranasal use of vitamin B12 includes symptoms such as headache, sore throat and rhinitis. Inhalation of Co alone can cause asthma (Barceloux, 1999a and Barceloux, 1999b) and simultaneous inhalation of cobalt and tungsten carbide (WC) particles induce the development of hard metal lung disease via ROS mechanisms. The International Agency for Research on Cancer (IARC) recently classified the mixture Co/WC as “probably carcinogenic to humans”. Cobalt alone was only classified as “possibly carcinogenic to humans”. Several studies reported that metallic cobalt acquires a higher genotoxicity when associated to WC or to other carbides.