Conjugation metabolism, principles

Testa B (2006) Principles of drug metabolism 2 hydrolysis and conjugation reactions. In Taylor JB, Triggle DJ (eds) Comprehensive medicinal chemistry II. Elsevier, Oxford, Sect 5.06... 

The concept of microbial models of mammalian metabolism was elaborated by Smith and Rosazza for just such a purpose (27-32). In principle, this concept recognizes the fact that microorganisms catalyze the same types of metabolic reactions as do mammals (32), and they accomplish these by using essentially the same type of enzymes (29). Useful biotransformation reactions common to microbial and mammalian systems include all of the known Phase I and Phase II metabolic reactions implied, including aromatic hydroxylation (accompanied by the NIH shift), N- and O-dealkylations, and glucuronide and sulfate conjugations of phenol to name but a few (27-34). All of these reactions have value in studies with the alkaloids. 

As in the case of propachlor mercapturic acid sulfoxide, the biological significance of xenobiotic mercapturic acids that contain oxidized sulfur is not known. Casida et al. (39) have reported that sulfoxidation of some thiocarbamate herbicides is a beneficial step in the detoxication process. However, cysteine conjugates can exhibit adverse biological activities. Smith (40) has reviewed work on the metabolism of the toxic principle in kale and has shown that C-S lyase action on S-methylcysteine sulfoxide produces the toxic principle. Virtanen ( ) has reviewed the processes in other plants that lead to the production of compounds with biological activity from -substituted cysteine sulfoxides. 

Although in principle the metabolic clearance of plasma T3 may occur via several pathways, direct deiodination of the inner ring of T3 by the type I enzyme seems of minor importance (Section 2.2). Also, glucuronidation in the liver does not represent an irreversible pathway of T3 elimination since enzymatic hydrolysis of the conjugate in the intestine allows for the reabsorption of free T3 (enterohepatic cycle). Further, the finding that plasma T3 clearance is not affected in patients with liver cirrhosis [115] suggests that hepatic metabolism of T3 by sulfation and subsequent deiodination is less important than in rats. It appears, therefore, that the type III deiodinase of extrahepatic tissues is a major site for the clearance of plasma T3 as it is also for the production of plasma rT3. 

Testa, B. Principles of drug metabolism 2 Hydrolysis and conjugation reactions. InADME-ToxApproaches (Testa, B., van de Waterbeemd, H., Eds.), Vol. 5. In Comprehensive Medicinal Chemistry (Taylor, J. B., Triggle, D.J., Eds.), 2nd Edition. Elsevier Oxford, 2007, pp. 133-166. 

The conversion of cholesterol into bile acids represents the most obvious example of the high capacity of the liver to convert lipid-soluble material into excretable water-soluble products. In principle, the reactions in the formation of bUe acids are very similar to those generally involved in the metabolism and detoxication of various lipids and drugs hydroxylations, oxidations, and conjugations. In contrast to detoxication reactions, however, some of the reactions are highly specific and at least one of the hydroxylations is subject to metabolic control. In view of the importance of the rate of elimination of cholesterol in diseases such as atherosclero-... 

Mock has described a very sensitive method (the limit of detection is around 5 fmol) for the detection of biotin and its metabolites, involving C18 reversed-phase HPLC separation followed by detection using an avidin-horseradish peroxidase conjugate (92). The principle of this method has already been discussed. This methodology has allowed the identification and quantification of biotin, bisnorbi-otin, biotin sulfoxides, and biotin sulfone in human and animal serum and urine. Furthermore, new biotin metabolites (tetranorbiotin sulfoxide and bisnorbiotin methyl ketone) were detected in human urine (114). This technique should potentiate more accurate studies on human biotin metabolism (see, e.g., 115). 

---