A great number of drugs and chemicals are reviewed which have been shown to stimulate lipid peroxidation in any biological system. The underlying mechanisms, as far as known, are also dealt with. Lipid peroxidation induced by iron ions, organic hydroperoxides, halogenated hydrocarbons, redox cycling drugs, glutathione depleting chemicals, ethanol, heavy metals, ozone, nitrogen dioxide and a number of miscellaneous compounds, e.g. hydrazines, pesticides, antibiotics, are mentioned. It is shown that lipid peroxidation is stimulated by many of these compounds. However, quantitative estimates cannot be given yet and it is still impossible to judge the biological relevance of chemical-induced lipid peroxidation.

Animals↗

PubMedDate not supplied

Rat hepatic vinyl chloride metabolites induce gene conversion in the yeast strain D7RAD in vitro and in vivo.

We have tested the genetic activity of gaseous vinyl chloride in vitro and in vivo using the gene-conversion system (trp5-12/trp5-27 leads to TRP+) in the yeast strain D7RAD. To induce, in vitro, TRP+ convertants with 2.5% gaseous vinyl chloride, a rat-liver microsomal system for metabolic activation of the vinyl chloride and dividing yeast cells are required. Neither a deficiency in excision repair (rad3) nor in the error-prone repair pathway (rad6) increased the vinyl-chloride-induced conversion frequencies compared with the repair-competent D7RAD strain. When logarithmically growing cells of the D7RAD strain were injected intravenously into male Wistar rats which inhaled 1% vinyl chloride in air for 24 h, a significant enhancement of the TRP+ conversion frequencies was found compared with that in cells re-isolated from untreated rats. These results indicate that vinyl chloride metabolites from the metabolizing hepatocytes diffuse into yeast cells, which accumulate in the liver capillaries. This supports the hypothesis that the endothelial cells of the liver sinuses, which have hardly any metabolic activity, but give rise to vinyl-chloride-induced hemangiotheliomas (rare type of liver tumor), are transformed by diffusible metabolites of the procarcinogen vinyl chloride.

Animals↗

PubMedDate not supplied

Ethane formation of isolated rat hepatocytes due to carbon tetrachloride.

Isolated rat hepatocytes incubated aerobically formed measurable amounts of ethane, a parameter for lipid peroxidation. This ethane formation increased several-fold due to carbon tetrachloride (CCl4) depending on its concentration. Cell damage as measured by trypan blue uptake and lactate dehydrogenase release poorly correlated with ethane formation. Ethane was not metabolized, whereas malondialdehyde (MDA), when added to isolated hepatocytes, decreased very rapidly. The results indicate that rather than MDA is a reliable parameter for lipid peroxidation occurring in isolated hepatocytes, and that a simple relationship between CCl4-induced lipid peroxidation and cell damage is not existing in isolated hepatocytes.

Animals↗

PubMedDate not supplied

Toxicity testing of chemical mixtures: some general aspects and need of international guidelines.

The topics discussed by the Working Group on Toxicity Testing of Chemical Mixtures included the following (1) the study designs and results from two real-life exposure scenarios as additional information to the various investigations reported at the conference; (2) the need to take into consideration low-level, long-term exposure (i.e. mimicking human exposure conditions) as well as the issue of limited resources in experimental toxicology studies; (3) the importance of exploring alternative and predictive toxicology methodologies to minimize animal use and to conserve resources; (4) the realization that interactive toxicity should include the consideration of physical and biological agents in addition to chemicals. Two specific studies reported at the conference were also discussed. A number of recommendations were made concerning the planning and implementation of toxicology studies on chemical mixtures.

Animals↗

PubMedDate not supplied

Effect of heavy metals on cellular growth, metabolism and integrity of cultured Chinese hamster kidney cells.

The effects of CdCl2, Na2CrO4, NaAsO2 and NiSO4 on cultured Chinese hamster kidney cells were studied over a concentration range for 48 h. Release of lactate dehydrogenase, a parameter of cell viability, was not closely related to cell proliferation except for Na2CrO4. A better correlation was obtained between glucose consumption and lactate production, and cellular growth. When studying toxic effects of metals in cell-culture systems, metabolic parameters should be determined in addition to cell viability and cellular growth. The results indicate that Chinese hamster kidney cells in culture might be useful to study mechanisms of metal-induced toxicity.

Animals↗

PubMedDate not supplied

Metabolic activation of norethisterone (norethindrone) to an irreversibly protein-bound derivative by rat liver microsomes.

Norethisterone, specifically labeled with tritium, was incubated with hepatic microsomes of rats. About 2% of 3H radioactivity was irreversibly incorporated into the microsomal protein. This protein binding of norethisterone (about 0.7-1.6 nmol/mg of microsomal protein) was dependent on oxygen, NADPH, substrate concentration, and microsomal protein content and could be inhibited by carbon monoxide. Glutathione and other cysteine derivatives with free sulfhydryl groups diminished the microsomal protein binding diminished the microsomal protein binding as did the addition of bovine serum albumin. Norethisterone-derived radioactivity was also irreversibly bound to albumin. Solvent-extraction and charcoal-adsorption methods were employed to prove the irreversible nature of this binding. After trypsin digestion of albumin and microsomal protein loaded with norethisterone, peptides which were labeled with 3H could be isolated. To explain our results, a metabolic bioactivation of norethisterone to norethisterone-4,5-epoxide, catalyzed by the microsomal mixed-function oxidase cytochrome P-450, is proposed.

Adsorption↗

PubMedDate not supplied

Photodynamic toxicity of hematoporphyrin derivatives to human keratinocytes in culture.

Human keratinocytes in culture were able to take up hematoporphyrin derivatives (HPDs) used during photodynamic chemotherapy of tumors. In the absence of light, HPDs showed no cytotoxic effects to keratinocytes. However, after irradiation with visible light, HPDs induced immediate cytotoxicity as measured by the neutral red uptake assay. On the other hand, cell attachment as measured by protein estimation was not affected. When the cells treated with HPDs and irradiated with light were cultured for a further 72 h, they partially lost their ability to attach to the collagen surface. Most of the cells remaining attached after 72 h were no longer viable following treatment with HPDs and light. All parameters measured depended on the intracellular concentration of HPDs used (7-50 ng/10(5) cells) and the time of irradiation (0-30 min). These results suggest that human keratinocytes are a good model to study cytotoxic effects of photodynamically active drugs. Further, keratinocytes were unable to recover after damage caused by HPDs and light.

Cells, Cultured↗