Biotransformation bioactivation process

The discussion that follows focuses on selected examples of metabolic transformations that may be linked to the formation of potentially neurotoxic metabolites. Although the number of well-characterized examples of such biotransformations is relatively few, it may be reasonable to speculate that the neurological disorders associated with long-term exposure to substances of abuse and some behaviormodifying medications may involve biochemical lesions mediated by chemically reactive metabolites. Thus, it may be important when attempting to assess the possible significance of metabolic bioactivation processes to appreciate that the chemical instability of reactive metabolites which can make the identification and characterization of their biological properties difficult. 

Generally, the formation of toxic metabolites is not the only pathway of biotransformation, and the overall metabolism is constituted toward detoxication and bioactivation processes. The toxic metabolites are themselves often further detoxified. The duality between a beneficial detoxication phenomenon (metabolism, drug resistance) and the occurrence of a toxic effect represents the cost for adaptability of metabolic enzymes to the diversity of xenobiot-ics. For those interested, a recent review applies the above chemistry to predict drug safety. 

Calu-3 cells have shown the ability to perform fatty acid esterification of budes-onide [132], In pre-clinical studies, this esterification results in a prolonged local tissue binding and efficacy, which is not found when the esterification is inhibited [133]. The precise mechanism remains undefined in that the identity of specific enzyme(s) responsible for this metabolic reaction is unclear [134], Assessment of the potential toxicity and metabolism of pharmaceuticals and other xenobiotics using in vitro respiratory models is still at its infancy. The development of robust in vitro human models (i.e., cell lines from human pulmonary origin) has the potential to contribute significantly to better understanding the role of biotransformation enzymes in the bioactivation/detoxication processes in the lung. 

While the term biotransformation generally implies inactivation and detoxification, there are exceptional cases where a metabolite is more chemically active or more toxic than the parent compound. In these situations, the processes of bioactivation and biotoxification are said to have occurred, respectively. An example of bioactivation is the formation of the commonly used drug acetaminophen from phenacetin in the liver (see Figure 3.2). The latter drug was once widely used as an analgesic agent but because of kidney toxicity has been replaced by other more potent, less toxic substitutes including, of course, acetaminophen itself. In this particular bioactivation pathway the process occurs via normal oxidative dealkylation. 

Biotransformation is not strictly related to detoxication, because in a number of cases the metabolites are more toxic than the parent pollutants, and in that case, the term of bioactivation or toxication is used. Metabolites may have comparable or greater toxicity in organism than the parent pollutant since during the biotransformation process functional groups are inserted into the pollutant by oxidation, reduction or hydrolysis reactions. 

Metabolism, or biotransformation, is the process of ehemical transformation of a toxicant to different structures, called metabolites, which may possess a different toxicity profile than the parent compound. Biotransformation affects both endogenous chemicals exogenous (xenobiotic) entities. Metabolism can result in a transformation product that is less toxie, more toxic or equitoxic but in general more water soluble and more easily excreted. Chemical modification can alter biological effects through toxication of a substance, also called bioactivation, which refers to the situation where the metabolic process results in a metabolite that is more toxic than the parent. If the metabolite demonstrates lower toxicity than the parent compound, the metabolic process is termed detoxication. These processes can involve both enzymatic and non-enzymatic processes, all of which should be familiar to undergraduate and graduate chemists. 

Biotransformation is a process in which one chemical compound is transformed into another by purified enzymes used as biocatalysts (Figure 2.1 la). Biotransformation can generate bioactive molecules, alter the physical properties of a compound, or produce enantiopure compounds [23-25]. 

FIGURE 9.1 A schematic representation of diet microbe interactions and how they shape immune function within the gut. Key metabolic processes within the human gut microbiota, especially carbohydrate fermentation, the enterohepatic circulation of bile acids and biotransformation of plant bioactive polyphenols by the gut microbiota play important roles in regulating both inflammatory and metabolic processes within the intestine, but also in other body tissues, like the liver, adipose tissue and brain, which are intimately involved in regulating whole-body glucose, lipid and energy metabolism, and also the chronic low-grade inflammation characteristic of metabolic diseases like diabetes, CVD, Alzheimer s and metabolic syndrome. 

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