Phase I transformations

Foreign compounds absorbed by mammals are subject to a variety of metabolic processes including functionalization and conjugation, also known as Phase I and Phase II metabolism, respectively. Common Phase I transformations indude oxidation, reduction, and hydrolysis while Phase II metabolism involves the biosynthesis of polar adducts (1). In general the metabolites of foreign compounds are more difficult to identify and quantitate than their parent structures due to their polarity and lower volatility. 

Note that an oxidation reaction often precedes conjugation because the oxidation reaction can generate hydroxyl and other groups to which groups such as glucuronic acid can be added. The oxidation reactions of xenobiotic compounds are often referred to as phase I transformations, and the conjugation reactions are referred to as phase II transformations. These reactions take... 

I) —20.5 ppm at 10°C). Peak intensity of the signal increases gradually up to 10°C compared with the low frequency peak. Moreover, the two peaks gradually shift to high frequency with increasing temperature. This means that ordered phase (I) transforms slowly with disordered phase (I) within the... 

Two phases can be distinguished in the pathways of biotransformation. Phase I involves addition of functionally reactive groups by oxidation, reduction or hydrolysis. Phase II consists of conjugation of reactive groups, present either in the parent molecule or after phase I transformation. Phenytoin, for example, is first hydroxylated by a phase I reaction and subsequently conjugated with glucuronic acid. The various phase I and phase II reactions are summarized in Tables 30.3 and 30.5. 

In the liver two phases of biotransformation reactions can take place phase I transformations that introduce polar groups (hydroxyls) in the molecule, and phase II reactions which include conjugations with glucuronic acid, sulphate, or glycine to yield water-soluble metabolites which are excreted in urine. 0-Methylations, to inactivate catechol moieties in these molecules, are also phase II reactions. Phase I reactions are not important in natural phenolic metabolites since they generally contain several polar hydroxyl groups). Phase II reactions increase the molecular weight of the phenolics and promote their secretion into bile. 

Substrate specificities can be broad and overlapping both among CYP family members and between CYPs and FMOs, and since metabolic transformations are often sequential (e.g. aliphatic hydroxylation being followed by oxidation by alcohol dehydrogenase, further oxidation to the acid, etc.), many enzymes and many metabolites can be involved in processing a single drug. Only a few of the most important enzymes involved in Phase I transformations have been mentioned here. For these and many others (monoamine oxidase, xanthine oxidase, etc.), further information can be found in the previously cited reviews. Bear in mind too that not all Phase I reactions are oxidative enzymes like carbonyl reductases are important in metabolism as well. 

Following Phase I Biotransformation, the next step in the process to eliminate chemical toxicants is called Phase II Biotransformation. In this process additional enzymes carry out reactions on the Phase I biotransformed products by adding functionalities that will make them very water soluble. This process is called conjugation because it links (or conjugates) the Phase I transformed product with another compound to produce a highly water-soluble product. The major kinds of conjugation in Phase II Biotransformation are ... 

Cytochrome P450 enzymes are the most widespread, active, and most versatile in their xenobiotic Phase I transformation activity. These enzymes are composed of heme-containing enzymes in the ferric ion state. In transformations the ferric ion is reduced to the ferrous ion that can bind Oj and CO. These enzymes basically add oxygen or remove hydrogen in a step-wise process to generate Phase I biotransformation products. Most cytochrome P450 transformations require an additional enzyme (co-enzyme) to assist in the transfer of electrons. Cytochrome P-450 enzymes carry out many kinds of oxidations - hydroxylations, epoxidations, heteroatom oxidations, N-hydroxylations, dealkylations, ester hydrolysis, and dehydrogenation. 

Oxidative phase I transformations involving cytochrome P450... 

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