Other Phase I reactions

The reactions involved in Phase I metabolism are not limited to those discussed in the previous sections. In theory, any suitable organic reaction could be 

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Oxidations are the most common reactions and ihe.se arc catalysed by an importam class of enzymes called the mixed function oxidases (cytuchronic lM5l)s). The substrate specilicity of this enzyme complex is very low ind m.Tny dilTcrem drugs can be oxidized (examples, top let l). Other phase I reactions are reductions (middle left) and hydrolysis t bottom left). 

The metabolism of foreign compounds (xenobiotics) often takes place in two consecutive reactions, classically referred to as phases one and two. Phase I is a functionalization of the lipophilic compound that can be used to attach a conjugate in Phase II. The conjugated product is usually sufficiently water-soluble to be excretable into the urine. The most important biotransformations of Phase I are aromatic and aliphatic hydroxylations catalyzed by cytochromes P450. Other Phase I enzymes are for example epoxide hydrolases or carboxylesterases. Typical Phase II enzymes are UDP-glucuronosyltrans-ferases, sulfotransferases, N-acetyltransferases and methyltransferases e.g. thiopurin S-methyltransferase. 

Beside the MMFO mediated (phase I) reactions there are a few other major reactions that are worthy of note. The two major ones involve ester hydrolysis and alcohol and aldehyde dehydrogenases. All mammalian species have an extensive ability to hydrolyze the ester bond. The products of the reactions then can go on to be further metabolized. In the pharmaceutical industry, this property has been utilized to synthesize prodrugs that is, chemicals that have desirable pharmaceutical properties (generally increased water solubility) that are not converted to their active moiety until hydrolyzed in the body. 

Phase II Reactions. As with phase I reactions, phase II reactions usually depend on several enzymes with different cofactors and different prosthetic groups and, frequently, different endogenous cosubstrates. All of these many components can depend on nutritional requirements, including vitamins, minerals, amino acids, and others. Mercapturic acid formation can be cited to illustrate the principles involved. The formation of mercapturic acids starts with the formation of glutathione conjugates, reactions catalyzed by the glutathione -transferases. 

Figure 7.2 shows the overall processes involved in a phase I reaction. Normally a phase I reaction adds a functional group to a hydrocarbon chain or ring or modifies one that is already present.4 The product is a chemical species that readily undergoes conjugation with some other species naturally present in the body to form a substance that can be readily excreted. Phase I reactions are of several types, of which oxidation of C, N, S, and P is most important. Reduction may occur on reducible functionalities by addition of H or removal of O. Phase I reactions may also consist of hydrolysis processes, which require that the xenobiotic compound have a hydrolyzable group. 

Discuss these reactions in terms of their significance for benzene toxicity and toxicological chemistry, phase I reactions, phase II reactions, and other aspects pertinent to benzene s effects on the body. 

In addition to the examples discussed above, a number of other xenobiotics are measured by their phase I reaction products. These compounds and their metabolites are listed in Table 20.1. These methods are for metabolites in urine. Normally, the urine sample is acidified to release the phase I metabolites from phase II conjugates that they might have formed, and except where direct sample injection is employed, the analyte is collected as vapor or extracted into an organic solvent. In some cases, the analyte is reacted with a reagent that produces a volatile derivative that is readily separated and detected by gas chromatography. 

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