Covalent binding index

The interaction of 1,1,2,2-tetrachloroethane with DNA, RNA and proteins of male Wistar rats and BALB/c mice in vivo was measured 22 h after intraperitoneal injection. The covalent binding index to liver DNA was about 500 (Colacci et al., 1987). 

Table 3. Correlation of hepatocarcinogenicity of chemicals in the rat with the covalent binding index for rat-liver DNA (adapted from Lutz (5))...

Metabolism studies in laboratory animals, including the rat, indicate that saccharin is not metabolized (Byard and Golberg, 1973 Mathews et al., 1973 Mineglshi et al., 1972). Saccharin is readily absorbed from the gastrointestinal tract and is rapidly excreted by the kidneys. Saccharin does not form covalently bound adducts with DNA in the bladder of the rat in an assay that would have detected one mole of saccharin per 10 moles of DNA phosphate (Lutz and Schlatter, 1977). By contrast, aflatoxln B has a covalent binding index in liver of 10,300 (Lutz, 1979) compared to a value for saccharin in the bladder of less than 0.05 (Lutz and Schlatter, 1977). Saccharin also appears to be nonmutagenic (Cranmer, 1980). 

Finally, we decided to measure the covalent binding of 3 to DNA in vivo, i.e. determine its covalent binding index (CBl). ... 

Bisnor- 4,6-dithiohexanoate or l,2-dithiolane 3-propanoate CBI covalent binding index CD circular dichroism CD = cysteamine dioxygenase... 

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. 

Seven carboxylic acid-bearing drugs (Figure 13) that have been reported to bind covalently to protein, in vitro and in vivo, with different degrees [27-34] of reactivity, were selected to evaluate the technique. The degrees of reactivity of the AG metabolites of these seven drugs were determined based on a reactivity index developed for each drug. It was found that the relative reactivity rank of the AG metabolites of these seven compounds was... 

Changes in the aggregation state may result in insolubilization of the protein, or its binding (not necessarily through covalent bonds) to other insoluble components. Thus, disappearance of a specific protein from the pool of soluble proteins in a given food may be detected by any of the techniques discussed above, and taken as a reliable index of process damage. A prime example of this simple approach to defining food quality at the molecular level may be the detection of individual whey proteins to define the quality of heat-treated milk. 

Zhou et al. (2011) evaluated 50 conditional binding constants (K) for biotic ligands from 27 studies and calculated mean ligand-specific conditional binding constants (K). They developed log K QSARs for five species using the Pearson and Mawby softeess parameter (a ), the covalent index (x r), the absolute value of... 

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