Reactive metabolites free radicals

Harris, M.L., Schiller, H.J., Reilly, P.M., Donowitz, M., Grisham, M.B. and Bulkley, G.B. (1992). Free radicals and other reactive oxygen metabolites in inflammatory bowel disease cause, consequence or epiphenomenon Pharmac. Ther. 53, 375-408. 

Alternative metabolic pathways involve ring-oxidation and peroxidation of arylamines. Although ring-oxidation is generally considered a detoxification reaction, an electrophilic iminoquinone (X) can be formed by a secondary oxidation of the aminophenol metabolite (18,19). Lastly, reactive imines (XI) can be formed from the primary arylamines by peroxidase-catalyzed reactions that involve free radical intermediates (reviewed in 20). 

Thus the competition between stimulatory and inhibitory effects of NO depends on the competition between two mechanisms the direct interaction of NO with free radicals formed in lipid peroxidation and the conversion of NO into peroxynitrite or other reactive NO metabolites. Based on this suggestion, Freeman and his coworkers [42-44] concluded that the prooxidant and antioxidant properties of nitric oxide depend on the relative concentrations of NO and oxygen. It was supposed that the prooxidant effect of nitric oxide originated from its reaction with dioxygen and superoxide ... 

Most reactive metabolites are electrophiles or free radicals. An electrophile is a molecule that is electron deficient and reacts with nucleophiles, which usually have a negative charge or a lone pair of electrons that can form a bond to the electrophile. Although there may be cases in which reactive metabolites are strong nucleophiles rather than electrophiles, there are no clear examples. 

Often but by no means always, reactive metabolites are produced by phase 1 reactions, commonly oxidation reactions. Therefore, cytochrome P-450 is regularly a culprit, and we can identify certain reactions, which are often involved. Reactive metabolites are often electrophiles, sometimes free radicals and occasionally nucleophiles. 

Donation of a proton or hydrogen atom to reactive metabolites or free radicals, respectively. 

In recent years, nitric oxide (NO) has emerged as one of the most interesting mediators of normal and patho physiological processes. NO is a highly reactive free radical, a lipophilic gas with a very short half-life in the range of 5 - 30 s under bioassay conditions (Palmer et al., 1987). NO is rapidly converted to nitrogen dioxide (N02), which again rapidly forms the more stable metabolites nitrite (N02 ) and nitrate (N03). 

Nitric oxide and NO synthases. Nitric oxide (NO) is a reactive free radical whose formula is often written as NO to recognize this characteristic. However, NO is not only a toxic and sometimes dangerous metabolite but also an important hormone with functions in the circulatory system, the immune system, and the brain.510 512 The hormonal effects of NO are discussed in Chapter 30, but it is appropriate here to mention a few reactions. Nitric oxide reacts rapidly with 02 to form nitrite (Eq. 18-61). 

Fig. 1. Schematic diagram showing the different mechanisms of action proposed for the antiulcer action of flavonoids. 1. Blockade of add secretion by decreasing histamine production or inhibiting the proton pump. 2. Bactericidal effect on H. pylori. 3. Antioxidative activity by scavenging free radicals and preventing ROM formation. 4. Potentiation of the mucosal protective factors. PAF platelet activating factor ROM reactive oxygen metabolites H2 histamine receptor 2 M muscarinic receptor G gastrin receptor.

Cocaine may be TV-demethyl ate d by the cytochrome P450 system to produce an active metabolite, norcocaine. Further breakdown produces A-hydroxynorcocaine and norcocaine nitroxide. Further metabolism produces a highly reactive free radical that is thought to be responsible for the hepatotoxicity observed in cocaine users.1... 

Reactive metabolites include such diverse groups as epoxides, quinones, free radicals, reactive oxygen species, and unstable conjugates. Figure 8.2 gives some examples of activation reactions, the reactive metabolites formed, and the enzymes catalyzing their bioactivation. 

Cell injury can be initiated by a number of mechanisms, such as inhibition of enzymes, depletion of cofactors or metabolites, depletion of energy (ATP) stores, interaction with receptors, and alteration of cell membranes. In recent years attention has focused on the role of biotransformation of chemicals to highly reactive metabolites that initiate cellular toxicity. Many compounds, including clinically useful drugs, can cause cellular damage through metabolic activation of the chemical to highly reactive compounds, such as free radicals, carbenes, and nitrenes (Chapters 7 and 8). 

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