Metabolites intrinsic reactivity

In conclusion, it is clear that a variety of stereoelectronic (internal) factors and external conditions favor a substantial positive charge in the transition state of diol epoxides as they undergo hydration or react with nucleophiles [115-118], Interpreting the reactivity of diol epoxides (or of numerous other electrophilic metabolites) in terms of toxification vs. detoxification is particularly difficult since toxicity depends as much on the nature of the endogenous nucleophile as on the intrinsic reactivity of the metabolites. 

In contrast, a number of alkene epoxides (10.3) are chemically quite stable, i.e., intrinsically less reactive than arene oxides. Examples of epoxide metabolites that have proven to be stable enough to be isolated in the absence of degrading enzymes include 1,2-epoxyoctane (10.4), 1,2-epoxycyclohex-ane (10.5), 1-phenyl-1,2-epoxy ethane (styrene oxide, 10.6), and cis- 1,2-diphenyl-1,2-epoxyethane (cfv-stilbene oxide, 10.7) [12], The same is true of alclofenac epoxide (10.8), hexobarbital epoxide (10.9), and a few other epoxides of bioactive compounds. 

This is often due to metabolites of a xenobiotic formed by bioactivation or biotransformation in the liver and not the parent compounds, and reactive metabolites are more likely to cause damage at the sites of phase I bioactivation reactions. Many different mechanisms cause hepatotoxicity and affect different cellular locations (Figures 3.3 and 3.4). Liver injury can be broadly classified as those injuries that are predictable and show a dose- and time-dependent pattern (type 1 lesions or intrinsic toxicity) and that occur in animals and are predictive of hepatic effects in man. Type... 

As outlined by de Weck (1971) in one of his basic contributions to our understanding of drug reactions, the ability of a simple chemical to induce an immune response, and consequently allergic reactions, rests on its ability to form those macromolecular conjugates in vivo or on the presence in the final pharmaceutical preparation of substances with chemical reactivity towards body constituents. For this to occur, it is either necessary that the vitamins possess some intrinsic chemical reactivity, contain some reactive decomposition product or byproduct, or that a reactive species is metabolically created in vivo (the reactive metabolite). 

When dealing with the individual vitamins we will review briefly what is known about such potentially reactive vitamin metabolites formed in vivo and the most likely reactive decomposition products, aggregation products, or byproducts formed in vitro. We will then also refer to possible intrinsic chemical reactivities of the individual vitamins themselves. 

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