Sly disease/β-glucuronidase deficiency/mucopolysaccharidosis VII
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
The disorder is transmitted in an autosomal recessive fashion via mutant genes on chromosome 7 [10]. Its incidence has been estimated at one in 300,000 live births in British Columbia [33]. The molecular defect is in the enzyme β-glucuronidase. (EC 3.2.1.31) [1, 34]. Cultured fibroblasts from patients accumulate sulfated mucopolysaccharide when incubated with 35SO4, and this abnormality is corrected by the addition of bovine liver β-glucuronidase to the medium [34]. Identity of the corrective factor and the glucuronidase was demonstrated by coelectrophoresis in polyacrylamide gel. Virtually complete deficiency has been demonstrated with a variety of synthetic substrates in leukocytes and in fibroblasts [34]. It has also been detected in serum [18]. The enzyme is a tetramer of 75 kDa subunits [35]. It is synthesized as a precursor protein and processed at the carboxyl end by the loss of the signal peptide [34]. Immunochemical studies have indicated the presence of cross-reacting material (CRM) in patients with the disease [36]. The measurement of enzyme activity has not correlated well with the degree of severity of phenotype.
Xenobiotic Biotransformation
Robert G. Meeks, Steadman D. Harrison, Richard J. Bull in Hepatotoxicology, 2020
Although glucuronide conjugation is considered to be primarily a detoxification reaction, there are examples where glucuronide conjugates are intermediates leading to toxic metabolites. The most notable is the induction of bladder cancer in workers in the dye industry exposed to arylamines such as 1- and 2-naphthylamine, 4-aminobiphenyl, and benzidine. After oxidation and then conjugation with glucuronide in the liver, the product is subsequently hydrolyzed by the acidic environment in the kidney, resulting in release of an electrophilic nitrinium compound. A similar example is the colon carcinogenicity of 2′3-dimethyl-4-aminobiphenyl. After oxidation and glucuronide conjugation in liver, the conjugate is secreted in the bile to the intestine, where bacterial β-glucuronidase liberates the glucuronide group to produce an electrophile. For the liver, glucuronidation participates in the bioactivation of N-hydroxy-ary lamines.
The Study of Drug Metabolism Using Radiotracers
Graham Lappin, Simon Temple in Radiotracers in Drug Development, 2006
The most commonly used deconjugation enzyme is β-glucuronidase from Helix pomatia, which contains both β-glucuronidase and sulfatase activity. Being a nonspecific enzyme, it has wide activity on a range of glucuronides and sulfates. Enzymes with higher specificities can be used for more targeted investigations. Glucuronidase from Escherichia coli is effective at hydrolyzing steroid glucuronides. Sulfatases can also be obtained, for example, from Aerobacter aerogens or Patella vulgate. Around 2000 Fishman units of β-glucuronidase (ex. Helix pomatia) in 0.2 M ammonium acetate buffer (pH 5.6) incubated for 4 to 6 h with 1 mL of sample is usually sufficient for putative conjugate hydrolysis. Enzymes from different sources have different pH optima, and these should be confirmed with the supplier. For β-glucuronidase, a positive control of phenolphthalein glucuronic acid is included to demonstrate the activity of the enzyme. As phenolphthalein is released during enzyme hydrolysis, a small amount of base will turn the solution pink. For sulfatase, the positive control is ρ-nitrophenol sulfate.
Effect of Saccharomyces Boulardii Cell Wall Extracts on Colon Cancer Prevention in Male F344 Rats Treated with 1,2-Dimethylhydrazine
Published in Nutrition and Cancer, 2018
Olivier Fortin, Blanca R. Aguilar-Uscanga, Khanh D. Vu, Stephane Salmieri, Monique Lacroix
β-glucosidase and β-glucuronidase are two bacterial enzymes who are able to deconjugate toxins and/or carcinogens that have been previously detoxified in the liver and secreted into the gut via the bile. Is it generally accepted that those enzymes may lead to high local concentrations of carcinogens in the gut, hence increasing risk of CRC carcinogenesis (17,46). More specifically, β-glucuronidase removes glucuronic acid from a compound detoxified by phase II enzymes hence releasing the carcinogenic compound in the colon (5). Similarly, β-glucosidase hydrolyses glycosidic bonds releasing nonreducing terminal glucosyl residues from an aglycon compound which may be carcinogenic or toxic for the colonic environment. Since glycosides are hydrolyzed in the colon by bacterial β-glucosidases, potentially toxic substances may be formed in the large intestine (16,47). Those bacterial enzymes are mostly produced by many Clostridium sp. (C. paraputrificum, C. clostridioforme, C. perfringens), Bacteroides sp. (B. vulgatis, B. uniforme, B. fragilis), Enterococcus sp., Peptostreptococcus sp., Staphylococcus sp., Ruminococcus (gnavus), Eubacterium sp., and Escherichia coli (46,48,49). For those reasons, a reduction in the activity of β-glucosidase and β-glucuronidase may lead to a reduced exposure to carcinogenic substances which potentially results to a reduction in the incidence of CRC.
Disposition and metabolism of ethylene glycol 2-ethylhexyl ether in Sprague Dawley rats, B6C3F1/N mice, and in vitro in rat hepatocytes
Published in Xenobiotica, 2021
AtLee T. D. Watson, Benjamin C. Moeller, Melanie Doyle-Eisele, Edwin Garner, Chad R. Blystone, Jacob D. McDonald, Suramya Waidyanatha
To determine the presence of conjugated metabolites, pooled urine from male rats administered 500 mg/kg [14C]EGEHE via gavage were incubated with β-glucuronidase, sulfatase, and acylase and were analysed under similar conditions. Enzymatic digestion caused modest changes in the relative peak areas for several of the major metabolites. Treatment of urine with β-glucuronidase resulted in the disappearance of three minor peaks between 5.4 and 8 min and appearance of two minor peaks at 1.6 and 4.5 min (Figure 2(B)). The largest peak at ∼8.5 min (55%, undigested) was reduced by 16, 23, and 29% following treatment with sulfatase, β-glucuronidase, and acylase, respectively, along with concomitant formation or slight increase in earlier peaks. For example, the second largest peak (∼7.5 min) increased by 34, 19, and 84% with incubation in sulfatase, β-glucuronidase, and acylase, respectively (Figures 2(B–D)). Urinary radiochromatograms following dermal application of [14C]EGEHE was similar to that following oral although fewer peaks were observed (chromatogram not shown). Urinary chromatograms in mice were similar to those of rats with minor differences; up to 16 peaks were detected including a small peak corresponding to parent [14C]EGEHE in chromatograms following both gavage administration and dermal application (chromatograms not shown).
A Neglected and Promising Predictor of Severe Hyperbilirubinemia Due to Hemolysis: Carboxyhemoglobin
Published in Fetal and Pediatric Pathology, 2020
Birol Karabulut, Baran Cengiz Arcagok
As with all such metabolites, a production–excretion balance exists during bilirubin metabolism. However, this balance may deteriorate owing to increased production or decreased excretion [1]. A decrease in the production of fixed excretion leads to developmental jaundice, while an increase in production can cause pathological jaundice. Developmental jaundice in newborns occurs at day 3–5 and peaks during days 3–7. Developmental jaundice is caused by aged fetal erythrocytes, immature uridine 5′-diphospho-glucuronyltransferase activity, and intestinal flora due to the β-glucuronidase enzyme function in breast milk; the total serum bilirubin (TSB) level may be as high as 17 mg/dl [2]. Pathological jaundice due to increased bilirubin production leads to earlier and higher levels of TSB, with abnormalities ranging from the subtle changes of bilirubin-induced neurologic dysfunction (BIND) to the most extreme cases of reversible acute bilirubin encephalopathy or the chronic, irreversible changes of kernicterus [3]. Regardless of the cause, the risk status should be determined before newborns are discharged from the hospital, and early detection is required to predict the peak value of bilirubin and prevent neurological dysfunction.
Related Knowledge Centers
- Catalysis
- Glucuronic Acid
- Glycosaminoglycan
- Hydrolysis
- Bilirubin
- Lysosome
- Carbohydrate
- Glycoside Hydrolase
- Heparan Sulfate
- Neonatal Jaundice