Glucuronidation types

Li B, Abliz Z, Fu G, Tang M, Yu S (2005) Characteristic fragmentation behavior of some glucuronide-type tritr penoid saponins using electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrom 19 381-390... 

Type I Crigler-Najjar syndrome is a rare autosomal recessive disorder. It is characterized by severe congenital jaundice (serum bilirubin usually exceeds 20 mg/dL) due to mutations in the gene encoding bilirubin-UGT activity in hepatic tissues. The disease is often fatal within the first 15 months of life. Children with this condition have been treated with phototherapy, resulting in some reduction in plasma bilirubin levels. Phenobarbital has no effect on the formation of bilirubin glucuronides in patients with type I Crigler-Najjar syndrome. A liver transplant may be curative. 

Reaction types noted oxidation (O), reduction (R), glycosylation (G), glucuronidation (GA) and sulfation (S). 

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. 

FIGURE 7.2 Examples of various types of glucuronide conjugates. 

Ester glucuronides are somewhat chemically reactive and can covalently bind to protein. It has been proposed that this type of metabolite is responsible for the idiosyncratic reactions associated with several drugs that are carboxylic acids as discussed in Chapter 8. 

In black children with acute lymphocytic leukemia (ALL) who were treated with etoposide, the wild-type UGTIAI 28 genotype (TA) has been associated with a higher clearance of etoposide, also indicating that the mutant genotype is responsible for less-potent glucuronidation (40). 

Oxcarbazepine is closely related to carbamazepine and is useful in the same seizure types, but it may have an improved toxicity profile. Oxcarbazepine has a half-life of only 1-2 hours. Its activity, therefore, resides almost exclusively in the 10-hydroxy metabolite, to which it is rapidly converted and which has a half-life similar to that of carbamazepine, ie, 8-12 hours. The drug is mostly excreted as the glucuronide of the... 

As an example of the first type of chiral effect, metabolism of the drug bufuralol may be considered. Hydroxy la tion in the V position only occurs with the (+) isomer, whereas for hydroxylation in positions 4 and 6, the (—) isomer is the preferred substrate (Fig. 5.3). Glucuronidation of the side chain hydroxyl group is specific for the (+) isomer. A further complication in human subjects is that the 1-hydroxylation is under genetic control, being dependent on the debrisoquine hydroxylator status (see below). The selectivity for the isomers for the hydroxylations is virtually abolished in poor metabolizers. 

Some oleanolic acid-type saponins were known to exhibit similar hepatoprotective activity [4, 7, 32, 42, 43, 44-46]. We also reported the hepatoprotective activity of Palustroside in which has a glucosyl carboxy group at C-28 [47]. As a part of our continuing study, we examined the preventive effects of five oleanolic acid-type glucuronides (90-95), Fig. (8), isolated from Dumasia tnmcata (Table 3) [48]. 

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