Binding to Cellular Macromolecules

As mentioned previously, most reactive metabolites are electrophiles that can bind covalently to nucleophilic sites on cellular macromolecules such as proteins, polypeptides, RNA, and DNA. This covalent binding is considered to be the initiating event for many toxic processes such as mutagenesis, carcinogenesis, and cellular necrosis, and is discussed in greater detail in the chapters in Parts IV and V. 

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Although metabolically-formed N-sulfonyloxy arylamides are strong electrophiles, bind to cellular macromolecules, and have long been considered ultimate carcinogens, their precise role in aryl-... 

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 nephrotoxic mode of action of tetrafluoroethylene is similar to that of hexachloro-butadiene. It is first metabolized to a cysteine conjugate, which is metabolized by cysteine conjugate /l-lyase to a reactive product that can bind to cellular macromolecules. 

Halothane (CFgCHBrCl), the first of the modern halogenated volatile anesthetics, was introduced into clinical practice in 1956. It is normally metabolized in an oxidative pathway forming bromide ions and trifluo-roacetic acid, neither of which has potential for tissue toxicity [36, 37]. Reductive metabolism of halothane takes place during low oxygen tension states in the liver [38]. This pathway has been linked to halothane-in-duced liver necrosis through production of free radicals that bind to cellular macromolecules [39, 40]. Reductive metabolism is also associated with production of fluoride ions [41], although the quantities produced are too small to have nephrotoxic importance. 

It is metabolized in vivo to a reactive form that covalently binds to cellular macromolecules, such as proteins and DNA, to cause toxicity. Agents that prevent these bindings can decrease the toxicity. 

The metabolites can bind to cellular macromolecules, such as proteins and DNA, to cause toxicity. 

Reactive metabolites of DBCP (e.g., epoxides) bind to cellular macromolecules. With testicular toxicity, DBCP may act by preventing differentiation of spermatogonia into mature sperm. 

The activation of DNT has been shown to be a multistep process involving metabolism in the liver, excretion into the bile, deconjugation of metabolites and further metabolism by the intestinal flora, re-uptake (enterohepatic transport) of metabolites into liver, and finally activation and binding to cellular macromolecules in the liver [56], More recent studies [57] involving rats pretreated with coal tar creosote, which potentiates the genotoxicity of 2,6-DNT, elucidated a complex interaction that balances metabolic activation, uptake, and detoxification. The study monitored intestinal flora enzyme activities, bacterial analysis, mutagenicity of urine samples, HPLC analysis, and hepatic DNA adducts over a five-week exposure period. The location of nitroreductase activity was an... 

It is evident from the previous sections that carcinogenicity (and mutagenicity) are composite properties which are influenced by metabolic activation of PAH to PAHDE and PAHTC and the subsequent binding to cellular macromolecules like DNA. The mutation induction may reflect different isomers of PAHDE s. This in turn may lead to a greater probability of error during repair or replication of sequences containing adducts of the more active diol epoxides. 

PAHs are enzymatically converted in mammalian cells to polar reactive intermediates, capable of covalently binding to cellular macromolecules. This metabolism is complex, involving many steps and enzymes. Most of these intermediate species are converted through secondary metabolic processes in the liver to form inactive products (e.g., glucoronides, sulfates, glutathione conjugates). These are excreted in urine and bile and it is only those products that escape these secondary reactions that react with nucleic acids and proteins, and probably lead to carcinogenesis. 

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