Chemically reactive metabolites toxicity determination

These strategies will fail, however, when the toxicity is caused by short-lived chemically reactive metabolites. Such metabolites are not easily isolated and thus their identity must be inferred from indirect evidence based on their ultimate decomposition products. Even if the chemically reactive metabolites were identified they would not be easily synthesized or purified. Moreover, their toxic potential is not easily studied because they would be inactivated during their passage from the sites of administration to their target organs. Clearly a different strategy must be employed to determine which chemically reactive metabolites are toxic and which are innocuous. 

Several years ago my colleagues and I devised a strategy to determine whether a given toxicity is caused by a chemically reactive metabolite. In developing the approach (1,2), we considered that chemically reactive metabolites conceivably could cause toxic reactions, such as a cellular necrosis, through several different mechanisms (Fig.l). 

It occurred to us, however, that we might be able to determine whether a toxicity was caused by chemically reactive metabolites by studying the effects of various inducers and inhibitors of the metabolism of the toxicant. According to our view, the covalent binding of the reactive metabolite to protein would be approximately proportional to the area under... 

Metabolism of a chemical plays an essential role in the toxicity evaluation of a chemical. It will usually result in the conversion to a more water-soluble metabolite, enhancing the excretion ratio and shortening the half-life of the chemical in vitro. However, biotransformation may also result in a metabolite with a higher reactivity, thus increasing the toxic potential of exposure to the chemical. Because in many cases in vitro systems do not account for this bioactivation, this factor is considered an important drawback of in vitro toxicity determinations [18]. 

Chemistry-based toxicity also involves exposure response, individual variability, and altered clearance. However, the proximal toxicant is typically a reactive chemical species. Several current systems are used for this purpose, such as mutagenicity (see Chapter 14) and carcinogenicity software programs, fragment-based chemistry and biology predictors, adduct determinations, and metabolite predictors. 

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