Metabolism reactive species formation

The oxidative metabolism leads to the formation of reactive species (epoxides, quinone-imines, etc.), which can be a source of toxicity. Consequently, slowing down or limiting these oxidations is an important second target in medicinal chemistry. Thus, the metabolism of halothan (the first modern general anaesthetic) provides hepatotoxic metabolites inducing an important rate of hepatitis the oxidation of the non-fluorinated carbon generates trifluoroacetyl chloride. The latter can react with proteins and lead to immunotoxic adducts [54], The replacement of bromine or chlorine atoms by additional fluorine atoms has led to new families of compounds, preferentially excreted by pulmonary way. These molecules undergo only a very weak metabolism rate (1-3%) [54,55]. 

The principal pathway by which unsubstituted and many substituted aromatic hydrocarbons are metabolized in mammals consists of the initial formation of arene oxides, which undergo a variety of enzymatic and nonenzymatic reactions prior to excretion of the resulting more polar, oxidized hydrocarbons via bile or urine. Taken together, these pathways represent an attempt on the part of the animal to detoxify or eliminate such nonpolar xenobiotic substances for which it has no apparent use. Although detoxification is the probable role of the arene oxide pathway, it is equally clear that chemically reactive species mediate this process. Thus, studies over the past several years have either implicated or established arene oxides in a causative role in such adverse biological reactions as cytotoxicity, mutagenesis, and carcinogenesis via covalent interaction of arene oxides with biopolymers,... 

In many cases, drug metabolites are less toxic than the corresponding parent drug. In some instances, drugs can undergo metabolic reactions that lead to the formation of reactive species [93], These reactive metabolites can bind to cell proteins and DNA to cause drug-induced toxicity and cell damage [94],... 

Similar studies with f/-ans-4-hydroxy-2-none-nal (HNE, a cytotoxic byproduct of biological membrane lipid peroxidation), indicate that it is also metabolically activated by CYP2B1 and -2B4 to a reactive species that binds irreversibly to their prosthetic heme"". Unlike the mechanism-based inactivation by aromatic aldehydes, strucmral analyses of the corresponding heme adduct (MW 770) revealed that the reaction proceeds without deformylation and involves an acyl carbon radical that partitions between addition to the heme and formation of the carboxylic acid"". Together these findings suggest that the P450-mediated metabolic activation of aldehydes is a versatile process wherein the enzyme may be inactivated via mechanistically diverse heme modifications. 

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