Microsomal oxidations aliphatic hydroxylation

Microsomal oxidations may be subdivided into aromatic hydroxylation aliphatic hydroxylation alicyclic hydroxylation heterocyclic hydroxylation N-, S-, and O-dealkylation N-oxidation N-hydroxylation S-oxidation desulfuration deamination and dehalogenation. 

Hepatic metabolism accounts for the clearance of all benzodiazepines. The patterns and rates of metabolism depend on the individual drugs. Most benzodiazepines undergo microsomal oxidation (phase I reactions), including TV-dealkylation and aliphatic hydroxylation. The metabolites are subsequently conjugated (phase II reactions) to form glucuronides that are excreted in the urine. However, many phase I metabolites of benzodiazepines are pharmacologically active, with long half-lives. 

The microsomal oxidations encountered include aliphatic side chain oxidations, aromatic hydroxylations, N-dealkylations, O- and S-dealkylations (which may also be viewed as ether cleavages), N-oxidations to N-oxides, and N-hydroxylations, and oxidation of divalent sulfur to sulfoxides. Representative examples are given in Table 3-1. 

Oxidations via microsomal P450 system Aliphatic hydroxylation (pentobarbital)... 

Disulfides (e.g., disulfiram), sulfoxides (e g., dimethylsulfoxide), N-oxides, double bonds such as those in progestational steroids, and dehydroxylation of aromatic and aliphatic hydroxyl derivatives are examples of reductions occurring in microsomal or nonmicrosomal (usually cytosol enzymes) fractions. 

In mammalian liver microsomes, cytochrome P-450 is not specific and catalyzes a wide variety of oxidative transformations, such as (i) aliphatic C—H hydroxylation occurring at the most nucleophilic C—H bonds (tertiary > secondary > primary) (ii) aromatic hydroxylation at the most nucleophilic positions with a characteristic intramolecular migration and retention of substituents of the aromatic ring, called an NIH shift,74 which indicates the intermediate formation of arene oxides (iii) epoxidation of alkenes and (iv) dealkylation (O, N, S) or oxidation (N, S) of heteroatoms. In mammalian liver these processes are of considerable importance in the elimination of xenobiotics and the metabolism of drugs, and also in the transformation of innocuous molecules into toxic or carcinogenic substances.75 77... 

Epoxidation and Aromatic Hydroxylation. Epoxidation is an extremely important microsomal reaction because not only can stable and environmentally persistent epoxides be formed (see aliphatic epoxidations, below), but highly reactive intermediates of aromatic hydroxylations, such as arene oxides, can also be produced. These highly reactive intermediates are known to be involved in chemical carcinogenesis as well as chemically induced cellular and tissue necrosis. 

This is different when free amines are formed as a result of an N-demethylation reaction. Free amines bind rather strongly to the oxidized and reduced hemoprotein and thus may cause product inhibitionVery stable complexes of different nature with the reduced hemoprotein have been reported after incubation of certain N-alkyl-ated amines of the amphetamine type with liver microsomes Recent studies on the mechanism of formation of these complexes support a mechanism ofN-hydroxyl-ation leading to aliphatic nitroso compounds which form tight complexes with the ferrous heme-sulfur protein... 

Multiple forms of CYPs exist in liver microsomes. These forms play a role in the oxidation (i.e., hydroxylation of aromatic, aliphatic, and alkyl groupings) of pyrethroid insecticides. The major isoforms in human liver include CYP 1A2, 2A6,... 

Another class of aliphatic oxidations catalyzed by microsomal monoxygenases is 0-dealkylation. The reaction involves cleavage of the alkyl-oxygen bond as shown by the lack of incorporation of oxygen-18 into the phenolic product, 4-hydroxyacetanilide, when 4-methoxyacetanilide was treated with microsomes in the presence of H2 0 and 18q2. The mechanism of such 0-dealkylations appears to involve hydroxylation of the alkyl moiety to form a hemlacetal or hemiketal which decon oses to form the 0-dealkylated product and, respectively, either an aldehyde or... 

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