Covalent binding cellular toxicity mechanism

The mechanism of benzene-induced toxicity appears to involve the concerted action of several benzene metabolites. Benzene is metabolized, primarily in the liver, to a variety of hydroxylated and opened-ring products that are transported to the bone marrow, where secondary metabolism occurs. Metabolites may induce toxicity both by covalent binding to cellular macromolecules and by inducing oxidative damage. Metabolites may also inhibit stromal cells, which are necessary to support growth of differentiating and maturing marrow cells. ... 

The most direct mechanism of hepatotoxicity is through specific interaction of a chemical with a key cellular component and consequential modulation of its function. More common mechanisms, however, involve secondary effects of toxicant interaction. These include depletion of cellular molecules, such as ATP and GSH free radical and oxidant damage, in particular to membrane lipids covalent binding of reactive metabolites to critical cellular molecules and collapse of regulatory ion gradients. The following discussion will highlight how these cellular and molecular mechanisms contribute to specific types of chemically induced hepatic lesions. 

One of the favored mechanisms for benzene toxicity or carcinogenicity is related to the covalent binding of benzene metabolites to cellular macromolecules. In mice administered radiolabeled benzene for relatively short durations, metabolites have been found covalently bound to liver, bone marrow, kidney,... 

Methods for Reducing Toxic Effects. Development of methods and practices that are specific for benzene is needed for reducing peak absorption, body burden and for interfering with the mechanism of action following benzene exposures. Since benzene metabolites are thought to play the major role in the toxicity and carcinogenicity, more information is needed about their covalent binding to nucleic acids and cellular macromolecules. This information would help the development of methods for possible... 

The mechanism of chloroform nephrotoxicity involves the oxidation of chloroform to trichloro-methanol by renal cytochrome P-450 isozymes (Figure 6). The trichloromethanol readily eliminates HCl to form the highly reactive toxicant phosgene (COCI2). The phosgene can (1) be detoxified by conjugation with two molecules of glutathione, (2) react with water to form two molecules of HCl and one molecule of CO2, or (3) covalently bind to renal macromolecules to disrupt cellular function and induce nephrotoxicity. 

Colby23 listed three major mechanisms of action of adrenotoxicants, mechanisms that are similar to actions of other toxicants. These are (1) covalent binding with critical cellular constituents, (2) formation of ROS, and (3) interference with the synthesis or function of cellular constituents such as proteins. 

The bioreduction of nitroaromatic compounds can proceed with the formation of the intermediary nitroso and hydroxylamine metabolites. That the fates of these intermediates in a microbial milieu are potentially numerous should be evident from this presentation of their chemical properties. Much of this information originated from research on the mechanisms by which arylhydroxylamine and nitrosoarene compounds cause toxicity in higher organisms. Covalent binding of these intermediates to cellular macromolecules can occur either directly in the case of nitrosoarene compounds and proteins, or indirectly in the case... 

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