Oxygenation, functional group metabolism

Hemiacetal derivatives of thiols (No. 1675) would be expected to undergo metabolism via the pathways described above for simple thiols. The thioether sulfur and the free thiol can undergo oxidation as described in more detail below, and methylation of the free thiol could also occur. The presence of oxygenated functional groups, such as an alcohol (No. 1703), aldehyde (No. 1692), acid (No. 1710),... 

Thioesters are hydrolysed by lipases and esterases (Kurooka et al., 1976) the rate of hydrolysis increases as the length of the carbon chain increases and decreases as the oxygenation of the carbon chain in the thiol moiety increases (Greenzaid Jenks, 1971). After hydrolysis, the resulting alcohol and carboxylic acid would participate in the metabolic pathways described above for sulfides containing oxygenated functional groups. 

Diisopentyl thiotartronate is anticipated to undergo simultaneous metabolism of sulfur and oxygenated functional groups (Gachon etal., 1988 Karim et al., 1988 Feng Solsten, 1991 Wilson et al., 1991 Black et al., 1993). Sulfoxide formation is usually the predominant metabolic detoxication pathway. Piperitone (No. 435) was evaluated by the Committee in 1998. It was concluded that piperitone was not a safety concern at current levels of intake. 

The presence of oxygenated functional groups also modifies the bioavailability of these compounds. It has been demonstrated recently that some ketocarotenoids are more rapidly absorbed and metabolized than other carotenes such as, for instance, lycopene. These xanthophylls do not present provitamin A activity, but their antioxidant action is more effective than that of p-carotene. The incorporation of the carotenoid pigments into cell structures is affected by the pigment stmcture and the presence of functional groups that may modify the interaction with other molecules. Such stmcture, as mentioned above, determines the effectiveness of the pigment s action. 

Segall and coworkers described the in vitro mouse hepatic microsomal metabolism of the alkaloid senecionine (159) (Scheme 34). Several pyrrolizidine alkaloid metabolites were isolated from mouse liver microsomal incubation mixtures and identified (222, 223). Preparative-scale incubations with mouse liver microsomes enabled the isolation of metabolites for mass spectral and H-NMR analysis. Senecic acid (161) was identified by GC-MS comparison with authentic 161. A new metabolite, 19-hydroxysenecionine (160), gave a molecular ion consistent with the addition of one oxygen atom to the senecionine structure. The position to which the new oxygen atom had been added was made evident by the H-NMR spectrum. The three-proton doublet for the methyl group at position 19 of senecionine was absent in the NMR spectrum of the metabolite and was replaced by two signals (one proton each) at 3.99 and 3.61 ppm for a new carbinol methylene functional group. All other H-NMR spectral data were consistent for the structure of 160 as the new metabolite (222). 

The role of oxygen functions in opioid ligands is complex, involving distribution, metabolism (especially conjugation) and binding interactions with the receptor, and assessment of the significance of a particular group requires information on each of these aspects. 

Oxidase, ligase, transferase, and hydrolase. In fact, the name oxidase is reserved for oxidations where a molecule of oxygen is present. Most oxidations encountered in metabolic pathways are catalyzed by dehydrogenase enzymes, which utilize cofactors such as FAD or NAD+ as the oxidant. Removal of functional groups without hydrolysis is done by lyase enzymes. The classihcation of enzymes is discussed in Section 8.1.3 (see Table 8.3 on page 193 of the text). 

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