Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.2.1.31 (beta-glucuronidase)
 7,680 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The in vitro formation rates of the phenolic (DPG) and acyl (DAG) glucuronides of diflunisal were investigated using rat liver microsomes. Preliminary studies showed that DAG hydrolysed rapidly (T1/2 = 12 min) when incubated in the presence of rat liver microsomes at pH 7.4 and 37 degrees. DPG was much more stable under the same conditions (T1/2 = 35 hr). Hydrolysis of DAG and DPG by rat liver microsomes was inhibited by 4 mM saccharolactone, a beta-glucuronidase inhibitor. The apparent Km and Vmax values for the formation of DAG in the absence and presence of 4 mM D-saccharic acid-1,4-lactone (saccharolactone) were the following: Km = 0.05 +/- 0.02 vs 0.08 +/- 0.02 mM and Vmax = 0.20 +/- 0.06 vs 0.43 +/- 0.07 nmol/min/mg protein (0 and 4 mM saccharolactone, respectively). The significant increase in apparent Vmax for DAG formation in the presence of saccharolactone can be explained by the inhibition of beta-glucuronidase-catalysed hydrolysis of DAG. Apparent Km and Vmax values for the formation rate of DPG were not affected by addition of saccharolactone to the incubation medium. These results indicate that beta-glucuronidase-catalysed hydrolysis of certain glucuronides formed during microsomal incubations may significantly affect the apparent glucuronidation rate due to the presence of a glucuronidation-deglucuronidation cycle.
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PMID:Glucuronidation of diflunisal by rat liver microsomes. Effect of microsomal beta-glucuronidase activity. 826 44

1. The glucuronidation of diflunisal to its phenolic (DPG) and acyl glucuronide (DAG) was measured in vitro using microsomes prepared from rat (n = 4) and human (n = 6) liver and kidney tissue. UGT activities towards bilirubin, 4-nitrophenol and (-)-morphine were also determined. 2. beta-Glucuronidase activity towards phenolphthalein glucuronide was much lower in microsomes prepared from human liver (45.2 +/- 3.1 Fishman Units/mg protein), human kidney (22.0 +/- 3.3 FU/mg), and rat kidney (25.1 +/- 2.5 FU/mg) as compared with rat liver (118.7 +/- 8.8 FU/mg). 3. The formation rate of DAG significantly increased when saccharo-1,4-lactone, a beta-glucuronidase inhibitor, was added to the rat liver microsomal incubation medium. beta-Glucuronidase inhibition, however, had little effect on the formation rate of DAG in human liver microsomes, and no effect in rat and human kidney microsomes. The formation of DPG was not affected by the microsomal beta-glucuronidase activity. 4. Unlike rat kidney microsomes, which only formed DAG, human kidney microsomes formed both diflunisal glucuronides. Formation of both diflunisal glucuronides in human kidney microsomes (Vmax = 0.97 +/- 0.21 and 0.27 +/- 0.07 nmol/min/mg for formation of DAG and DPG respectively) represented 60-70% of the activity found in liver microsomes (Vmax = 1.58 +/- 0.32 and 0.40 +/- 0.08 nmol/min/mg for formation of DAG and DPG respectively). 5. These results demonstrate that the in vitro glucuronidation rate of diflunisal may be affected by the microsomal beta-glucuronidase activity particularly when using rat liver microsomes. Our results also demonstrate that the human kidney has an important UGT-activity towards diflunisal.
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PMID:Glucuronidation of diflunisal in liver and kidney microsomes of rat and man. 886 97

Many non-steroidal anti-inflammatory drugs (NSAIDs) which form acyl glucuronide conjugates as major metabolites have shown an antiproliferative effect on colorectal tumors. This study assesses the extent to which rearrangement of an acyl glucuronide metabolite of a model NSAID into beta-glucuronidase-resistant isomers facilitates its passage through the small intestine to reach the colon. Rats were dosed orally with diflunisal (DF), its acyl glucuronide (DAG) and a mixture of rearrangement isomers (iso-DAG) at 10 mg DF equivalents/kg. The parent drug DF appeared in plasma after all doses, with maximum concentrations of 20.5+/-2.5, 28.8+/-8.3 and 11.0+/-1.6 microg DF/ml respectively, obtained at 3.8+/-0.3, 3.6+/-1.8 and 7.5+/-0.9 hr after the DF, DAG and iso-DAG doses respectively. At 48 hr, 16.2+/-3.3, 19.8+/-0.8 and 42.9+/-10.1% of the doses respectively were recovered in feces, with < or = 1% remaining in the intestine. About half of each dose was recovered as DF and metabolites in 48 hr urine: for DF and DAG doses, the majority was in the first 24 hr urine, whereas for iso-DAG doses, recoveries in the first and second 24 hr periods were similar. The results show that hydrolysis of both DAG and iso-DAG, and absorption of liberated DF, occur during passage through the gut, but that these processes occur more slowly and to a lesser degree for iso-DAG. The intrinsic hydrolytic capacities of various intestinal segments (including contents) towards DAG and iso-DAG were obtained by incubating homogenates under saturating concentrations of DAG/iso-DAG at 37 degrees C. Upper small intestine, lower small intestine, caecum and colon released 2400, 3200, 9200 and 22800 microg DF/hr/g tissue plus contents respectively from DAG substrate, and 18, 10, 140 and 120 microg DF/hr/g tissue plus contents respectively from iso-DAG substrate. The much greater resistance of iso-DAG to hydrolysis appears attributable to its resistance to beta-glucuronidases. The data suggest that in rats dosed with DF, DAG excreted in bile would be substantially hydrolysed in the small intestine and liberated DF reabsorbed, but that portion which rearranges to iso-DAG would likely reach the colon.
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PMID:Rearrangement of diflunisal acyl glucuronide into its beta-glucuronidase-resistant isomers facilitates transport through the small intestine to the colon of the rat. 1176 4