Phase II metabolic reactions

The concept of microbial models of mammalian metabolism was elaborated by Smith and Rosazza for just such a purpose (27-32). In principle, this concept recognizes the fact that microorganisms catalyze the same types of metabolic reactions as do mammals (32), and they accomplish these by using essentially the same type of enzymes (29). Useful biotransformation reactions common to microbial and mammalian systems include all of the known Phase I and Phase II metabolic reactions implied, including aromatic hydroxylation (accompanied by the NIH shift), N- and O-dealkylations, and glucuronide and sulfate conjugations of phenol to name but a few (27-34). All of these reactions have value in studies with the alkaloids. 

Drugs must also be considered as foreign compounds, and an essential part of drug treatment is to understand how they are removed from the body after their work is completed. Glucuronide formation is the most important of so-called phase II metabolism reactions. Aspirin, paracetamol, morphine, and chloramphenicol are examples of drugs excreted as glucuronides. 

Conjugations. Conjugation reactions are Phase II metabolic reactions that are enzymatically catalyzed and involve the attachment of small polar molecules (glucuronic acid, sulphate, amino acids) to the drug. This, in turn, makes the drug more water soluble and... 

Phase I and Phase II metabolic reactions require amino acids for enzyme synthesis. A diet that is deficient in amino acid sources (proteins) can result in the individual not synthesizing significant enough enzyme quantities to... 

The metabolism of xenobiotics proceeds at different rates for different individuals. This is because of genetic variations. Two examples demonstrate this point. CYP450 enzyme production (required for Phase I metabolism) varies by as much as 30% in healthy individuals. TV-acetyltransferase reaction rates (an example of a Phase II metabolism reaction) vary widely. Some individuals acetylate rapidly and others slowly, with the slow acety-lators having lower toxic thresholds. 

List the major phase I and phase II metabolic reactions. 

Acetylcholine and methacholine are metabolized in the body by hydrolysis of the ester bond. Is this a phase I or phase II metabolic reaction The Skill Keeper Answer appears at the end of the chapter. 

Phase II metabolism The reaction of a phase I metabolite with an endogenous compound, e.g. glucuronic acid, to form a polar compound that is eliminated from the body. 

As inhibitors of certain enzyme reactions and apoptosis related to the development of cancer (Naasani et al, 1998 Yang et al, 2001), specifically by selective induction or modification of phase I and phase II metabolic enzymes so as to increase the formation and excretion of detoxified metabolites of carcinogens. 

The predicted metabolites are also the starting point for the phase II metabolic prediction, to find where glucuronidation could occur. All the probable metabolites obtained from CYP metabolism reactions are submitted to a possible phase II reaction catalyzed by UGTs, using the UGT structure(s) as a template. The accessibility component is computed in the UGTcavity to prioritize glucuronic acid transfer. The final metabolite structures are then reported in graphical output or saved to a file. 

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