Metabolism phase 11 reactions

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. 

Zinc (Zn) deficiency is teratogenic in rats, and fetal skeletal defects are prominent. Embryofetal zinc deficiency secondary to changes induced by substances in maternal Zn metabolism is a well-established mechanism for developmental toxicity (29-31). Several substances, including urethane and alpha-hederin cause similar malformations as Zn deficiency in rodents. A number of mechanistic studies have shown that these substances act via an acute-phase reaction induction of metallothionein in the maternal liver which binds systemically available Zn in the pregnant animal. This results in a systemic redistribution of Zn. As a consequence the substances produce a transient but developmentally adverse Zn deficiency in the... 

Nevertheless, for the production of the flavour-active aromatic alcohol derivatives, such as the corresponding aldehydes and acids, metabolic engineering approaches have to compete with conventional oxidative biocatalysis starting from the natural alcohol as a substrate. For instance, the whole-cell oxidation system based on Pichia pastor is AOX already described in Sect. 23.4.1.2 can also be used to convert benzyl alcohol to benzaldehyde in aqueous media although product inhibition restricted the final product concentration to about 5 g L h indicating the need for aqueous-organic two-phase reaction media [51]. Phenylacetalde-... 

Metabolism of foreign compounds is not necessarily detoxication. This has already been indicated in examples and will become more apparent later in this book. This may involve activation by a phase 1 or phase 2 pathway or transport to a particular site followed by metabolism. Phase 1 reactions, particularly oxidation, can be responsible for the production of reactive intermediates such as epoxides, quinones, hydroxy la mines, and free radicals, which lead to toxicity. However, phase 2 reactions can also result in toxicity in some cases. 

Biotransformation refers to changes in xenobiotic compounds as a result of enzyme action. Reactions not mediated by enzymes may also be important. As examples of nonenzymatic transformations, some xenobiotic compounds bond with endogenous biochemical species without an enzyme catalyst, undergo hydrolysis in body fluid media, or undergo oxidation-reduction processes. However, the metabolic phase I and phase II reactions of xenobiotics discussed here are enzymatic. 

Table 3.1 Examples of metabolic phase I and phase II reactions...

Hydrolytic cleavages, along with oxidations, reductions, alkylations, and dealkylations, constitute phase I reactions of drug metabolism. These reactions subsume all metabolic processes apt to alter drug molecules chemically and take place chiefly in the liver. In phase II (synthetic) reactions, conjugation products of either the drug itself or its phase I metabolites are formed, for instance, with glucuronic or sulfuric acid... 

A pattern of liver necrosis similar to that caused by bromobenzene is observed in patients who ingest massive doses of acetaminophen (Table 16.2). This toxic reaction also has been produced experimentally in mice and rats and is thought to occur in two phases. An initial metabolic phase in which acetaminophen is converted to a reactive iminoquinone metabolite is followed by an oxidation phase in which an abrupt increase in mitochondrial permeability, termed mitochondrial permeability transition (MPT), leads to the release of superoxide and the generation of oxidizing nitrogen and peroxide species that result in hepatocellular necrosis (13, 14). 

Formation of sulfate esters is one of the metabolic conjugation reactions (Phase II reactions, see Chapter 34). Sulfates of estradiol," s giucose," menadiol," and... 

Formation of sulfate esters is one of the metabolic conjugation reactions (phase II reactions, see Chapter 31). Sulfates of estradiol, glucose, menadiol, and hydro-xyethyl-theophylline have been prepared (Fig. 36.9). As a rule sulfuric acid esters, compared with their phosphoric analogues, are resistant to enzymatic hydrolysis in and their conversion to the parent drug is questionable. 

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