Covalent binding to macromolecules

Reactive chemicals or their reactive intermediates, such as free radicals and other electrophilic species, may form essentially irreversible covalent bonds with adjacent macromolecules, such as proteins, lipids, and DNA, resulting in the formation of adducts. Covalent adducts can disrupt the normal function of such macromolecules and result in a broad spectrum of toxic responses. These may range from localized transient skin irritation to systemic target organ toxicity (such as hepatotoxicity, neurotoxicity, and renal toxicity), genotoxicity, or carcinogenicity. 

However, the adverse effects of APAP bioactivation are not observed until high doses are administered, where there is sufficient depletion of natural reserves of antioxidants, for example, reduced glutathione (GSH). Depletion of GSH exacerbates arylation of cellular proteins by NAPQI and amplifies oxidative stress from ROS, eventually leading to a drop in cellular ATP levels and cell death. Hence it is not the advent of covalent binding of reactive intermediates that is solely responsible for APAP toxicity, but rather a combination of events in which protein binding plays an important role. 

8-trans-diol-9,10-epoxide, which is considered the ultimate carcinogen of BaP. 

The genetic consequence of BaP-N2-guanine adduct formation can be associated with errors in base pairing during DNA replication, for example, base substitutions. 

If these occur in critical genes, such as the tumor suppressor gene p53 [45], they can lead to mutations and ultimately cancer, if the mistakes are not identified and corrected by DNA repair processes. 

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Some chemicals that strongly bind to biological receptors (ligands) can produce toxicity directly. However, most toxic chemicals are not intrinsically reactive and must be metabolized to reactive intermediates that often covalently bind to macromolecules (DNA, proteins, etc.), and, if present at a sufficient level, lead to toxicity. Metabolism generally serves to make lipophilic compounds more hydrophilic in order to facilitate excretion through the liver and into the bile for excretion into the feces or through the kidneys and into the urine. This process generally... 

Oxidative stress and covalent binding to macromolecules. Oxidation to the epoxide occurs via a tetrahedral intermediate, which can form either an epoxide or a phenol directly (see the scheme below). The epoxide can covalently bind nucleophiles, such as DNA or proteins, to open up the epoxide to a phenol and make toxic covalent adducts. The phenols can be further oxidized to bisphenols, which can in turn form quinones. Quinones can cause serious oxidative damage to cells through radical pathways, or can alkylate N- or S-nucleophiles, such as glutathione and glycine. 

PAHs are known to undergo covalent binding to macromolecules. They are potent inducers of Cyt P450. [17]. They can also be activated twice by CYP to dihydrodiol peroxides. Carcinogenicity is affected by both the number of rings and the methyl substitution, so that the toxicity pattern for the series below is as shown below [18], with toxicity increasing to the right (two separate series of molecules) ... 

Furans can also undergo covalent binding to macromolecules [20]. Furans, such as 8-methoxypsoralen, are epoxidized by Cyt P450 to yield a highly electrophilic species, which is so reactive that it covalently modifies an amino acid residue of CYP itself and thus inactivates the enzyme irreversibly (hence it is also in the class of suicide inhibitors) [21]. 

Nitrosamines Dimethyl nitrosamine Covalent binding to macromolecules [23]. 

Benzoyl peroxide forms radicals that are involved in its covalent binding to macromolecules. Its biological effects are inhibited by antioxidants. 

Radiosensitizing effect in hypoxic cells [89] toxicity to hypoxic cells [102, 112, 115, 116] DNA damage [112], antitrichomonal activity [137], structure-activity [115, 116] inhibition of T. cruzi growth at concentrations that do not stimulate 0 and H202 production (reduced metabolites of benznidazole are involved through covalent binding to macromolecules in its trypanocidal and toxic effects) [133]... 

Metabolic products vary with the type of enzyme inductions. In fetal rat livers, several compounds, such as 1- or 2-hydroxy-, cis- and ra s-dihydroxy-, 11,12-dihydroxy-ll,12-dihydro-, and 1- and 2-keto-3-cholanthrene have been identified. Most frequently, it is the liver that produces a variety of electrophilic reactants that covalently bind to macromolecules. Metabolism or bioactivation may also be extramicrosomal or be carried out by fetoplacental tissue or gut bacteria. 

Covalent binding to macromolecules leading to liver necrosis... 

Limited information is available on the biotransformation of carbon disulfide in humans, and the metabolic products of carbon disulfide are not completely known. In animals and humans the proposed metabolic pathways involved in the metabolism of carbon disulfide (Beauchamp et al. 1983) are depicted in Figure 2-3, reactions i-x. Reaction i has been demonstrated in in vivo animal studies and in in vitro assays. Reactions ii-v are proven by in vitro studies, while products of reactions vi-ix are the results of proposed metabolic pathways of carbon disulfide in animals and humans. Carbon disulfide is metabolized by cytochrome P-450 to an unstable oxygen intermediate (reaction i). The intermediate may either spontaneously degrade to atomic sulfur and carbonyl sulfide (reaction ii) or hydrolyze to form atomic sulfur and monothiocarbonate (reaction iii). The atomic sulfur generated in these reactions may either covalently bind to macromolecules (reaction iv) or be oxidized to products such as sulfate (reaction v). 

Hoag, M.K.P., A.J. Trevor, A. Kalir, and N. Castagnoli (1987). NADPH-dependent metabolism, covalent binding to macromolecules, and inactivation of cytochrome(s) P450. Drug Metab. Dispos. 15, 485-490. 

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