Glucuronide formation enzymes

Figure 14.5 Intestinal resveratrol metabolic pathway proposed after oral administration using Caco-2 monolayers. SULT and UGT enzymes shown in bold represent the predominant contribution to sulfate and glucuronide formation.

Ionizing Radiation. In general, ionizing radiation reduces the rate of metabolism of xenobiotics both in vivo and in enzyme preparations subsequently isolated. This has occurred in hydroxylation of steroids, in the development of desulfuration activity toward azinphosmethyl in young rats, and in glucuronide formation in mice. Pseudocholinesterase activity is reduced by ionizing radiation in the ileum of both rats and mice. 

An inspiring, and likely the first, example for the therapeutic application of enzyme induction to affect the metabolic fate of an endogenous substance has recently been reported by Yaffe and his associates (71) phenobarbital treatment has been used to prevent hyperbilirubinemia by inducing the glucuronyl transferase, enhanced glucuronide formation enabled increased bilirubin excretion and resulted in decreased serum bilirubin concentration. 

Invariably, the conjugates produced are even more polar and water soluble than are the primary metabolites. For example, glucuronide formation adds three new hydroxyl groups and one carboxyl group. As a result conjugates are of low or no toxicity and almost without exception exhibit no pharmacological activity. The enzymes that catalyze these synthetic reactions are also found mainly in the liver. 

Species differences in the metabolism of drugs and other foreign compounds are known to occur (see Williams, 1967 Smith, 1968) and this can affect the amount of a compound excreted in the bile. Thus, in the domestic cat, glucuronide formation is at a low level compared with other species (Robinson and Williams, 1958). The poor ability of the cat to form glu-curonides is apparently due to a deficiency of glucuronyl transferase (Dutton and Gniig, 1957). This enzyme catalyzes the following reaction ... 

Glucuronyl transferases A group of enzymes that catalyze the formation of conjugates between glucuronide and a xenobiotic (usually a phase I metabolite). 

There is no information regarding the metabolism of 3,3 -dichlorobenzidine in children. However, N-acetylation (as discussed above) in humans is likely done by one of two families of N-acetyltransferases. One of these families, NAT2, is developmentally regulated (Leeder and Kearns 1997). Some enzyme activity can be detected in the fetus by the end of the first trimester. Almost all infants exhibit the slow acetylator phenotype between birth and 2 months of age. The adult phenotype distribution is reached by the age of 4-6 months, whereas adult activity is found by approximately 1-3 years of age. Also, UDP-glucuronosyltransferase, responsible for the formation of glucuronide conjugates, seems to achieve adult activity by 6-18 months of age (Leeder and Kearns 1997). These data suggest that metabolism of 3,3 -dichlorobenzidine by infants will differ from that in adults in extent, rate, or both. 

Metabolism - Following a 400 mg dose of C-indinavir, 83% and 19% of the total radioactivity was recovered in feces and urine, respectively radioactivity caused by parent drug in feces and urine was 19.1% and 9.4%, respectively. Seven metabolites have been identified 1 glucuronide conjugate and 6 oxidative metabolites. In vitro studies indicate that cytochrome P450 3A4 (CYP3A4) is the major enzyme responsible for formation of the oxidative metabolites. 

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