摘要:

AbstractCytotoxicity associated with exposure to quinones has generally been attributed to either redox cycling, and the subsequent development of“oxidative stress”and/or to their interaction with cellular nucleophiles, such as protein and non-protein sulfhydryls. Glutathione (GSH) is the major non-protein sulfhydryl present in cells, and conjugation of potentially toxic electrophiles with GSH is usually associated with detoxication and excretion. However, this review discusses the biological (re)activity of quinone-thioethers. For example, quinone-thioethers are (1) capable of redox cycling (2) substrates for, and inhibitors of, a variety of enzymes (3) methemoglobinemic (4) potent nephrotoxicants (5) DNA reactive and (6) may contribute to quinone-mediated carcinogenicity and neurotoxicity. The ubiquitous nature of quinones, and the high intracellular concentrations of GSH, ensures that cells and tissues will be exposed to quinone-thioethers. The toxicological importance of quinone-thioethers in quinone-mediated toxicities therefore deserves further attention.

ISSN:1040-8444    

DOI:10.3109/10408449209146309

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

AbstractThe possibilities and limitations of using mercapturic acids and protein and DNA adducts for the assessment of internal and effective doses of electrophilic chemicals are reviewed. Electrophilic chemicals may be considered as potential mutagens and/or carcinogens. Mercapturic acids and protein and DNA adducts are considered as selective biomarkers because they reflect the chemical structure of the parent compounds or the reactive electrophilic metabolites formed during biotransformation. In general, mercapturic acids are used for the assessment of recent exposure, whereas protein and DNA adducts are used for the assessment of semichronic or chronic exposure. 2-Hydroxyethyl mercapturic acid has been shown to be the urinary excretion product of five different reactive electrophilic intermediates. Classification of these electrophiles according to their acid-base properties might provide a tool to predict their preference to conjugate with either glutathione and proteins or with DNA. Constant relationships appear to exist in the cases of 1,2-dibromoethane and ethylene oxide between urinary mercapturic acid excretion and DNA and protein adduct concentrations. This suggests that mercapturic acids in some cases may also play a role as a biomarker of effective dose. It is concluded that simultaneous determination of mercapturic acids, protein and DNA adducts, and other metabolites can greatly increase our knowledge of the specific roles these biomarkers play in internal and effective dose assessment. If the relationship between exposure and effect is known, similar to protein and DNA adducts, mercapturic acids might also be helpful in (individual) health risk assessment.

ISSN:1040-8444    

DOI:10.3109/10408449209146310

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

AbstractMonocrotaline (MCT) is an 11-membered macrocyclic pyrrolizidine alkaloid (PA) that causes a pulmonary vascular syndrome in rats characterized by proliferative pulmonary vasculitis, pulmonary hypertension, and cor pulmonale. Current hypotheses of the pathogenesis of MCT-induced pneumotoxicity suggest that MCT is activated to a reactive metabolite(s) in the liver and is then transported by red blood cells (RBCs) to the lung, where it initiates endothelial injury. While several lines of evidence support the requirement of hepatic metabolism for pneumotoxicity, the mechanism and relative importance of RBC transport remain undetermined. The endothelial injury does not appear to be acute cell death but rather a delayed functional alteration that leads to disease of the pulmonary arterial walls by unknown mechanisms. The selectivity of MCT for the lung, as opposed to that of other primarily hepatoxic PAs, appears likely to be a consequence of the differences in hepatic metabolism and blood kinetics of MCT. A likely candidate for a reactive metabolite of MCT is the dehydro-genation product monocrotaline pyrrole (MCTP). Secondary or phase II metabolism of MCT through glutathione (GSH) conjugation has been characterized recently and appears to represent a detoxification pathway. The role of inflammation in the progression of MCT-induced pulmonary vascular disease is uncertain. Both perivascular inflammation and platelet activation have been proposed as processes contributing to the response of the vascular media. This review presents the experimental evidence supporting these hypotheses and outlines additional questions that arise from them.

ISSN:1040-8444    

DOI:10.3109/10408449209146311

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

AbstractThe uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.

ISSN:1040-8444    

DOI:10.3109/10408449209146312

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

AbstractToxicants can be converted in vivo by a variety of biotransformation reactions into substances that are more, equally, or less noxious than the parent compound. Although conjugation with glutathione is a process that usually results in less harmful products, these products might subsequently form new metabolites that exert more toxicity than the parent compound. These conjugation reactions are catalyzed by several classes of glutathione-S-transferase isoenzymes and thus result in the urinary or biliary excretion of N-acetyl-L-cysteine-S-conjugates (mercapturic acids). Inasmuch as GSH-S-transferase activity varies among different tissues, urinary excretion of mercapturic acids might reflect tissue-specific toxicity. Urinary mercapturic acids are biomarkers of internal and, in some cases, effective dose. The utility of these markers is, however, limited to times shortly after exposure. Studies on possible human deficiencies in some GSH-S-transferases might help us better understand interindividual variations in susceptibility to different toxicants and thus the differences in the pathway of mercapturic acid excretion pattern.

ISSN:1040-8444    

DOI:10.3109/10408449209146313

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor