Toxicity covalent binding

Gibson FD, Pumford NR, Samokyszyn VM, et al. Mechanism of acetaminophen-induced hepa to toxicity Covalent binding versus oxidative stress. Chem Res Toxicol 1996 9 580. 

Covalent binding of chemicals to biological macromolecules can also cause toxicity. During biotransformation and metabolic activation, chemical compounds can be changed to free radicals, which have an unpaired... 

Graham, D.G. Tiffany, S.M. Bell, W.R., Jr. and Gutknecht, W.F. Autooxidation versus covalent binding of quinones as the mechanism of toxicity of dopamine, 6-hydroxydopamine and related compounds toward C1300 neuroblastoma cells in vitro. Mol Pharmacol 14 644-653, 1978. 

Zhou, S., Chan, E., Duan, W. et al. (2005) Drug bioactivation, covalent binding to target proteins and toxicity relevance. Drug Metabolism Reviews, 1, 41-213. 

The presence of chemically reactive structural features in potential drug candidates, especially when caused by metabolism, has been linked to idiosyncratic toxicity [56,57] although in most cases this is hard to prove unambiguously, and there is no evidence that idiosyncratic toxicity is correlated with specific physical properties per se. The best strategy for the medicinal chemist is avoidance of the liabilities associated with inherently chemically reactive or metabolically activated functional groups [58]. For reactive metabolites, protein covalent-binding screens [59] and genetic toxicity tests (Ames) of putative metabolites, for example, embedded anilines, can be employed in risky chemical series. 

Gillette, J.R. 1994. Commentary. Perspective on the role of chemically reactive metabolites of foreign compounds in toxicity. I. Correlation of changes in covalent binding of reactivity metabolites with changes in the incidence and severity of toxicity. Biochem. Pharmacol. 23, 2785. 

Whilst chloramines are less reactive than HOC1, they are longer-lived and so can diffuse away from their site of production. Those formed from lipophilic amines are especially toxic because they can permeate membranes. Chloramines are toxic for a number of reasons they can oxidise sulphydryl or sulphur-ether groups, they are unstable and can be hydrolysed to release chlorine in the form of HOC1 or NH2C1, they can react with iodide to form iodine and they can covalently bind proteins. 

Ilett KF, Reid WD, Sipes IG, et al. 1973. Chloroform toxicity in mice Correlation of renal and hepatic necrosis with covalent binding of metabolites to tissue macromolecules. Exp Mol Pathol 19 215-229. 

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. ... 

Studies in mice have shown that selective covalent binding of VDC occurs in the proximal tubules, the liver lobules, and the mucosa of the upper respiratory tract and corresponds to sites of potential toxicity. Additional events such as depletion of glutathione appear to be necessary for VDC-induced cell death to occur. 

It is tempting, given the above, to conclude that any degree of covalent binding of drug species to macromolecules will lead to a toxic response. However, this is clearly not the case as there are plenty of examples where covalent binding has had no toxicological consequence. 

From a purely pragmatic perspective, it is clear that reactive metabolites are linked with toxicity and that a circumstantial link can be made to idiosyncratic toxicides. Consequently, even though the mechanism of this toxicity is not fully understood, since assays are available to measure the potential for bioactivation in an ideal world one would not carry this liability forward. Conversely, it is not an ideal world, all drug molecules have challenges and the definition of therapeutic index (i.e., the ratio between the toxic exposure and the therapeutic exposure) is critical. Covalent binding of reactive metabolites to macromolecules is a crude measure and not a full predictor of toxicity and it is well known that toxicity can be ameliorated by a lower dose. Furthermore, the so-called definitive assays require radiolabeled drug material which is expensive and generally slow to produce. 

Roberts, S.A., Veronica, F.P. and Jollow, D.J. (1990) Acetaminophen structure-toxicity studies In vitro covalent binding of a non-hepatotoxic analog, 3-hydroxy-acetanilide. Toxicology and Applied Pharmacology, 105, 195-208. 

Takakusa, H., Masumoto, H., Yukinaga, H., Makino, C., Nakayama, S., Okazaki, O. and Sudo, K. (2008) Covalent binding and tissue distribution/retention assessment of drugs associated with idiosyncratic drug toxicity. Drug Metabolism and Disposition The Biological Fate of Chemicals, 36 (9), 1770-1779. 

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