Oxidative stress in chemical toxicity

The toxic effects of compounds which undergo redox cycling via enzymatic one-electron reduction are reviewed. First of all, the enzymatic reduction of these compounds leads to reactive intermediates, mainly radicals which react with oxygen, whereby superoxide anion radicals are formed. Further oxygen metabolites are hydrogen peroxide, singlet oxygen and hydroxyl radicals. The role of these oxygen metabolites in toxicity is discussed.The occurrence of lipid peroxidation during redox cycling of quinonoide compounds, e.g., adriamycin, and the possible relationship to their toxicity is critically evaluated. It is shown that iron ions play a crucial role in lipid peroxidation induced by redox cycling compounds.DNA damage by metal chelates, e.g., bleomycin, is discussed on the basis of findings that enzymatic redox cycling of a bleomycin-iron complex has been observed. The involvement of hydroxyl radicals in bleomycin-induced DNA damage occurring during redox cycling in cell nuclei is claimed. Redox cycling of other substances, e.g., aromatic amines, is discussed in relation to carcinogenesis.Other chemical groups, e.g., nitroaromatic compounds, hydroxylamines and azo compounds are included. Other targets for oxygen radical attack, e.g., proteins, are also dealt with.It is concluded that oxygen radical formation by redox cycling may be a critical event in toxic effects of several compounds if the protective mechanisms of cells are overwhelmed.Dedicated to Professor Dr. med. Herbert Remmer on the occasion of his 65th birthday     

Oxygen radical formation and DNA damage due to enzymatic reduction of bleomycin-Fe(III)

Aerobic incubations of bleomycin, FeCl₃, DNA, NADPH, and isolated liver microsomal NADPH-cytochrome P-450 reductase resulted in NADPH and oxygen consumption and malondialdehyde formation, indicating that the deoxyribose moiety of DNA was split. All parameters measured depended on the active enzyme, bleomycin and FeCl₃. In the absence of oxygen malondialdehyde formation was very low.When bleomycin, FeCl₃ and the reductase were incubated with methional ethene (ethylene) was formed, suggesting that during the enzyme-catalyzed redox cycle of bleomycin-Fe(III/II) hydroxyl radicals were formed. Ethene formation also depended on oxygen, NADPH, the enzyme, bleomycin, and FeCl₃.During aerobic incubations of bleomycin, FeCl₃, NADPH, and isolated liver nuclei oxygen and NADPH were consumed and malondialdehyde was formed. Oxygen and NADPH consumption and malondialdehyde formation depended on bleomycin and FeCl₃. In the absence of oxygen malondialdehyde was not formed. These results indicate that nuclear NADPH-cytochrome P-450 reductase redox cycles the bleomycin-Fe(III/II) complex and that the reduced complex activates oxygen, whereby hydroxyl radicals are formed which damage the deoxyribose of nuclear DNA.Dedicated to Professor Dr. med. Herbert Remmer on the occasion of his 65th birthday     

Studies on acute toxic effects to keratinocytes induced by hematoporphyrin derivatives and laser light

Summary Human epidermal keratinocytes were grown in culture and the uptake of hematoporphyrin derivatives (HPDs) used in photodynamic therapy was estimated. Keratinocytes loaded with HPDs were irradiated with laser light of 632 nm generated by a helium-neon laser and cell toxicity was determined by the trypan blue exclusion test and the measurement of enzyme release. With increasing intracellular concentration of HPDs and with increasing intensity of the laser light, an increasing number of cells took up trypan blue and released the cytosolic enzyme lactate dehydrogenase and the lysosomal enzyme acid phosphatase after 1 h incubation of the irradiated cells at 37°C. Cytotoxicity was less pronounced when the irradiated cells were incubated at 0°C indicating the involvement of enzyme reactions in cell death. No lipid peroxidation as measured by malondialdehyde and ethane formation was detectable. Our results suggest that during photodynamic therapy with HPDs and laser light epidermal keratinocytes may be seriously damaged. The data indicate that not lipid peroxidation but rather the activation of lysosomal enzymes is responsible for the cytotoxicity observed.     

SMAP – Standardisierte medizinische Notrufabfrage in der Rettungsleitstelle der Feuerwehr Hamburg

A consistently high quality ambulance dispatch can only be achieved through the imposition of fixed standards. This can only be achieved through the use of a proven standard medical dispatch system. The article describes the decision criteria for the introduction of this system in the emergency medical system (EMS) control room of the Hamburg Fire Department. The Advanced Medical Priority Dispatch System (AMPDS) is presented which was introduced in 2008. The conditions for the introduction of the AMPDS and the practical experiences in the first 2 years of system implementation are reported.     

Redox cycling of bleomycin-Fe(III) by an NADH-dependent enzyme, and DNA damage in isolated rat liver nuclei

Isolated rat liver nuclei were incubated aerobically with bleomycin (BLM) and FeCl3 in the presence of NADH. An increase in NADH and oxygen consumption was observed accompanied by DNA cleavage as shown by gel electrophoresis. Malondialdehyde (MDA) was also formed, which partly derived from DNA indicating an oxidative cleavage mechanism. BLM and NADH were obligatory to provide these effects, whereas FeCl3 could be omitted, without a complete loss of the activities mentioned above. This was explained by the presence of some iron in the nuclei. NADPH was consumed to a lesser extent compared to NADH and was less effective with respect to O2 consumption and MDA formation. It could be excluded that mitochondrial or microsomal contaminations in nuclear preparations were responsible for the effects observed. The results suggest that the BLM-Fe(III)-complex can be repeatedly reduced (redox cycled) by NADH- (and NADPH-) dependent reductases of liver nuclei to BLM-Fe(II) which is known to form reactive oxygen species and to damage DNA. It is concluded that the enzymatic reduction of a BLM-metal complex in the cell nucleus may be an essential step in the cytotoxic activity of bleomycin.