Glucuronyl transferase in liver

S8) to be located in the microsome fraction of the liver. The neonatal development of this conjugating system has been studied by Brown et al. (B17) in the guinea pig. They were unable to detect the presence of bilirubin glucuronyl transferase in liver microsomes from fetal and newborn animals and, using o-aminophenol as a glucuronyl acceptor, were... 

Guinea pig (a) Inhibition of UDP-glucose dehydrogenase and UDP-glucuronyl transferase in liver and intestine by piperine [14]... 

Potentially, individuals with low activities of the enzymes phenol sulfotransferase and glucuronyl-transferase may be more susceptible to phenol toxicity. Persons with ulcerative colitis may have an impaired capacity to sulfate phenol (Ramakrishna et al. 1991), which may increase the amount of unchanged phenol that is absorbed following oral exposure. Neonates may also be more susceptible to toxicity from dermally-applied phenol because of increased skin permeability and proportionately greater surface area. A study in which 10-day-old rats were more sensitive to lethality following oral exposure to phenol than 5-week-old or adult rats (Deichmann and Witherup 1944) further suggests that the young may be more sensitive to phenol. (For a more detailed discussion please see Section 2.6.) Because phenol is a vesicant, individuals with sensitive skin or pulmonary incapacity may be more sensitive to phenol. Individuals with kidney or liver diseases that impair metabolism or excretion of phenol and phenol metabolites may be more susceptible to phenol. 

Bl. Bakken, A. F., Effects of unconjugated bilirubin on bilirubin-UDP-glucuronyl transferase activity in liver of newborn rats. Pediat. Res. 3, 205-209 (1969). 

B17. Black, M., Billing, B. H., and Heirwegh, K. P. M., Determination of bilirubin UDP-glucuronyl transferase activity in needle-biopsy specimens of human liver. Clin. Chim. Ada 29, 27-35 (1970). 

This is the most common single metabolic reaction undergone by drugs, which occurs in the liver. These reactions are catalyzed by a family of enzymes known as uridine diphosphate (UDP) glucuronyl transferases. These enzymes are present in liver, kidney, intestine and lungs. 

It has now been established that in common with many other glu-curonides, bilirubin glucuronide can be synthesized in the adult rat, rabbit, mouse, and guinea pig liver by the enzymatic transfer of glucuronic acid from uridine diphosphate glucuronic acid to an acceptor substance, namely, bilirubin (Fig. 3) (B17, G5, L3, L5, S8). The transferring enzyme (glucuronyl transferase) has been shown by Schmid et al. 

Subsequent studies have shown (e.g. 5,6, Table I) that the liver of newborns is indeed deficient in enzymes needed not only for drug metabolism but also for the elimination of natural products. For example, because of the lack of UDP-glucuronyl transferase resulting in the inability to dispose of bilirubin, the newborn is at risk for brain damage by kernicterus. That PEP carboxykinase, the key catalyst of gluconeogenesis de novo is absent at 7 months and still at low titers 3 days after birth (Table I), probably contributes to the fact that transient hypoglycemia (which can also cause brain damage) represents a hazard to full term as well as premature infants. The immaturity of the hepatic enzyme composition imposes limitations on the choice of nutrients used to supplement or re-... 

Inhibitors of HA synthesis have valuable therapeutic potential in the prevention of cancer invasion and metastasis. A novel inhibitor of HA synthesis has been identified, 4-methylumbelliferone (4-MU). However, this inhibitor does not have a direct effect on the HAS enzymes. Rather, it is glucuronidation of the inhibitor that depletes UDP-glucuronyl transferase stocks, required for the formation of UDP-glucuronic acid. Thus, it is substrate depletion that appeeirs to be the mechanism of action. The inhibitor is effective in both vertebrate and bacterial systems [131]. 4-MU has been shown to inhibit liver metastases of melanoma following oral administration in mice [132]. 

Glucuronyl transferases are membrane-bound enzymes primarily associated with the endoplasmic reticulum of liver cells. Glucuronidation takes place to a lesser extent in cells of many other tissues as well. Sulfate conjugation represents the important metabolic alternative to glucuronidation being mediated by a soluble enzyme system (2). Glucuronidation is favored for lipophilic compounds while the lower molecular weight, hydrophilic xenobiotics in the cytosol are preferred substrates for sulfation. 

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