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PubMed1983

Tissue distribution of mammalian aldose reductase and related enzymes.

Activities of aldose reductase (AR) and related NADPH-dependent enzymes were examined in extracts of human, cat, dog, guinea pig, mouse, monkey, pig, rabbit, rat and sheep lenses and a variety of other tissues. The activity of the tissues against DL-glyceraldehyde, D-glucuronic acid, and 3-pyridinecarboxaldehyde (PCA) was determined. High glyceraldehyde:glucuronic acid activity ratios, a characteristic of aldose reductase, were found in all lenses, except from mouse. An analytical thin-layer isoelectric focusing system which separates the mammalian NADPH-dependent enzymes was developed. AR appears to be present as two or more isozymes in all mammalian lenses studied with the exception of mouse. Other tissues contain one or more isozymes which have the same isoelectric point and substrate specificity as the AR present in the lens of that species. This AR activity, however, may represent only a small proportion of the total NADPH reducing activity present. AR and HDH isozymes reduce the aromatic substrate, PCA, and thus have the general characteristics of an aldehyde reductase.

Alcohol Oxidoreductases↗
PubMed1991

Metabolism and cytotoxicity of eugenol in isolated rat hepatocytes.

The metabolism and toxic effects of eugenol (4-allyl-2-methoxyphenol) were studies in isolated rat hepatocytes. Incubation of hepatocytes with eugenol resulted in the formation of conjugates with sulfate, glucuronic acid and glutathione. The major metabolite formed was the glucuronic acid conjugate. Covalent binding to cellular protein was observed using [3H]eugenol. Loss of intracellular glutathione and cell death were also observed in these incubations. Concentrations of 1 mM eugenol caused a loss of over 90% of intracellular glutathione and resulted in approximately 85% cell death over a 5-h incubation period. The loss of the majority of glutathione occurred prior to the onset of cell death (2 h). The effects of eugenol were concentration dependent. The addition of 1 mM N-acetylcysteine to incubations containing 1 mM eugenol was able to completely prevent glutathione loss and cell death as well as inhibit the covalent binding of eugenol metabolites to protein. Conversely, pretreatment of hepatocytes with diethylmaleate to deplete intracellular glutathione increased the cytotoxic effects of eugenol. These results demonstrate that eugenol is actively metabolized in hepatocytes and suggest that the cytotoxic effects of eugenol are due to the formation of a reactive intermediate, possibly a quinone methide.

Animals↗
PubMed1999

(2-O-alpha-D-galactopyranosyl-4-O-methyl-alpha-D-glucurono)-D-xylan from Eucalyptus globulus Labill.

An unusual heteroxylan composed of galactosyl, 4-O-methyl-glucuronosyl and xylosyl residues with molar ratio 1:3:30 was isolated from the wood of Eucalyptus globulus Labill. The results of linkage analysis, supported by data of 1H, 2D 1H-1H COSY and 13C NMR spectroscopy, revealed that the polysaccharide is a (2-O-alpha-D-galactopyranosyl-4-O-methyl-alpha-D- glucurono)-D-xylan with a (1-->4)-linked beta-D-xylopyranosyl backbone branched at O-2 by short side chains composed of terminal 4-O-methyl-alpha-D-glucuronic acid and of 4-O-methyl-alpha-D-glucuronic acid substituted at O-2 with alpha-D-galactose.

Carbohydrate Conformation↗
PubMed1978

Isolation of six novel phosphoinositol-containing sphingolipids from tobacco leaves.

A concentrate of phosphosphingolipids from tobacco leaves has been resolved into two groups by chromatography on diethylaminoethylcellulose. The first group eluted contains no acetyl residues, whereas the second group contains one N-acetyl/mol of phosphorus. Three lipids from each group have been purified by chromatography on Porasil columns. The chemical composition of these six novel lipids shows them to be related to the previously characterized phosphosphingolipids PSL-I, N-acetylglucosamine[glucuronic acid, inositol phosphate]ceramide and PSL-II, glucosamine[glucuronic acid, inositol phosphate] ceramide [Kaul, K.,and Lester,R. L. (1975), Plant Physiol. 55, 120]. The novel lipids are: PSL-IA, PSL-I-[Ara2Gal2]; PSL-IB, PSL-I-[Ara3Gal2]; PSL-IC, PSL-I-[Ara4Gal2]; PSL-IIA, PSL-II-[Ara3Gal]; PSL-IIB, PSL-II-[Ara2or3Gal2]; PSL-IIC, PSL-II-[Ara2Gal2Man]. The unusual finding of unacetylated hexosamine in the PSL-II group of lipids appears not to be an artifact, as suggested by experiments involving rapid harvesting and processing of the tobacco leaves. Some of the fractions obtained by chromatography on diethylaminoethylcellulose appear to contain phosphosphingolipids with 16 or more sugar residues.

Phosphatidylinositols↗
PubMed1984

Ascorbic acid in thyroidectomized rats. I) Biosynthesis and catabolism.

Thyroidectomized rats showed a decrease in ascorbic acid and dehydroascorbic acid, with almost no alterations in the diketogulonic acid in liver and kidney. Total ascorbic acid in urine was found to be increased, whereas glucuronic acid in urine decreased significantly. There were no significant changes in the activities of ascorbic acid synthesizing enzymes. Activities of the degrading enzymes were found to increase significantly in the liver, with no remarkable change in their activities in kidney. Daily administration of thyroxine for 10 days to thyroidectomized rats normalized the activities of dehydroascorbatase and 2,3 diketoaldonate decarboxylase in the liver, whereas single administration of thyroxine on the 7th day after thyroidectomy could not bring about such restoration. It seems that thyroxine has no direct role on ascorbic acid metabolism in rats.

Animals↗
PubMed1982

An unusual heparan sulfate isolated from lobsters (Homarus americanus).

An unusual heparan sulfate was isolated from lobsters (Homarus americanus). The polysaccharide has a composition and properties intermediate to heparin and the more common heparan sulfates. The sulfate and D-glucuronic acid content is high, while anticoagulant activity is low. The major repeating unit appears to consist of D-glucuronic acid and D-glucosamine N-O-disulfate. Some N-acetyl groups are present, the content of L-iduronic acid O-sulfate is low, and monosulfated or nonsulfated disaccharide-repeating units (very common in heparan sulfates) appear to be very rare. The data obtained again emphasize the heterogeneity of heparan sulfates and the need for adequate characterization when dealing with unusual or unexplored sources.

Animals↗
PubMed1983

Effect of several xenobiotics on the activities of enzymes affecting ascorbic acid synthesis in rats.

The dietary addition of several xenobiotics, such as PCB, DDT, aminopyrine, chloretone, BHT and BHA, caused significant increases in the ascorbic acid in urine and liver of rats. The administration of all types of xenobiotics used in the present experiments increased the activity of hepatic UDP-glucose dehydrogenase (1.3-2.8-fold), and the administration of PCB, DDT, BHT or BHA significantly increased the activity of hepatic UDP-glucuronyl transferase (2.2-13.1-fold). The activity of beta-glucuronidase was slightly increased with feeding of PCB, DDT, chloretone or aminopyrine. However, the activity of hepatic UDP-glucuronic acid pyrophosphatase, the conversion of D-glucuronic acid or D-glucuronolactone into L-ascorbic acid and the activity of hepatic L-gulonolactone oxidase did not increase with the administration of PCB or DDT. It is suggested that the increases in the activities of UDP-glucose dehydrogenase and UDP-glucuronyl transferase would have a major role in the stimulation of ascorbic acid synthesis in xenobiotic treated rats.

Aminopyrine↗
PubMed1991

Inhibition of glucuronidation of benzo(a)pyrene phenols by long-chain fatty acids.

Long-chain fatty acids inhibit glucuronidation of benzo(a)pyrene phenols in perfused liver; therefore, this study was designed to investigate interactions of fatty acids with beta-glucuronidase, glucuronosyl transferase, and energy supply. In beta-glucuronidase-deficient C3H/He mice, infusion of oleate (250 microM) increased the release of free benzo(a)pyrene phenols from 14 to 33 nmol/g/h and decreased release of glucuronides into the perfusate from 25 to 17 nmol/g/h. Rates of accumulation of glucuronides in the liver were also diminished from 11 to 4 nmol/g/h after infusion of oleate (250 microM). Fatty acids did not affect the release of benzo(a)pyrene metabolites into bile, and the ratio of free phenol to glucuronide production was increased from 0.57 to 1.30. A similar trend was observed in livers from DBA/2 mice that have beta-glucuronidase. Rates of hydrolysis of benzo(a)pyrene-O-glucuronide were not altered in isolated microsomes by addition of oleoyl coenzyme A (CoA) or octanoyl CoA (10- approximately 100 microM). Thus, we conclude that fatty acids do not alter glucuronidation by acting on beta-glucuronidase. The concentration of cofactors (UDP-glucuronic acid, UDP-glucose, and adenine nucleotides) involved in hepatic conjugation was not altered by infusion of concentrations of oleate (300 microM) that inhibited glucuronidation in perfused livers. When oleate concentrations were increased to 600 microM, UDP-glucuronic acid and UDP-glucose decreased 44 and 49%, respectively, and the ATP:ADP ratio declined concomitantly. Oleoyl CoA inhibited UDP-glucuronosyl transferase noncompetitively (half-maximal inhibition, 10 microM) in microsomes with 3-hydroxy-benzo(a)pyrene or p-nitrophenol as substrate. In contrast, octanoyl CoA was a very poor inhibitor of transferase activity. Inhibition of the transferase by oleoyl CoA was increased markedly by treatment with detergents (Triton X-100), i.e., half-inhibition of glucuronosyl transferase was obtained with about 2 microM oleoyl CoA. Inhibition of UDP-glucuronosyl transferase by oleoyl CoA was also increased in a dose-dependent manner by albumin, possibly due to increasing access of the CoA derivative to the enzyme. Collectively, these data indicate that fatty acids diminish glucuronidation via the formation of acyl CoA compounds that inhibit UDP-glucuronosyl transferase noncompetitively.

Animals↗
PubMed2003

Quantification of hepatic carbohydrate metabolism in conscious mice using serial blood and urine spots.

In vivo studies of hepatic carbohydrate metabolism in (genetically modified) conscious mice are hampered by limitations of blood and urine sample sizes. We developed and validated methods to quantify stable isotope dilution and incorporation in small blood and urine samples spotted onto filter paper. Blood glucose and urinary paracetamol-glucuronic acid were extracted from filter paper spots reproducibly and with high yield. Fractional isotopomer distributions of glucose and paracetamol-glucuronic acid when extracted from filter paper spots were almost identical to those isolated from the original body fluids. Rates of infusion of labeled compounds could be adjusted without perturbing hepatic glucose metabolism. This approach was used in mice to find the optimal metabolic condition for the study of hepatic carbohydrate metabolism. In fed mice, no isotopic steady state was observed during a 6-h label-infusion experiment. In 9-h-fasted mice, isotopic steady state was reached after 3 h of label infusion and important parameters in hepatic glucose metabolism could be calculated. The rate of de novo glucose-6-phosphate synthesis was 143 +/- 17 micromol kg(-1) min(-1) and partitioning to plasma glucose was 79.0 +/- 5.2%. In 24-h-fasted mice, abrupt changes were noticed in whole body and in hepatic glucose metabolism at the end of the experiment.

Acetaminophen↗
PubMed1998

Relationship between oxidation and conjugation metabolism of skatole in pig liver and concentrations of skatole in fat.

High concentrations of skatole in fat of some intact male pigs are a major cause of boar taint. In this study, we investigated the effect of oxidative and conjugative metabolism of skatole in liver on the concentrations of skatole in the fat of intact male pigs. In Trial 1, 18 Yorkshire intact males were equally divided into two treatments with high (mean, .42; SD, .26 ppm) and low (mean, .06; SD, .02 ppm) fat skatole levels. There was an increased rate of skatole metabolism, an increased glucuronidation activity, and a decreased sulfation activity toward 2-naphthol in liver from pigs with high skatole levels (P < .05). In Trial 2, Swedish Yorkshire x F4 European Wild Pig intact males were used. Among skatole metabolites that were produced in incubations with liver microsomes, pro-MII was conjugated with glucuronic acid and sulfate, and metabolite F-1 was conjugated with glucuronic acid. The rates of formation of various skatole metabolites and conjugation of pro-MII were evaluated for 22 pigs with different levels of cytochrome P4502E1 in the liver. The formation of F-1 and sulfation of pro-MII were negatively correlated with fat skatole levels (r = -.59, and r = -.56, respectively) and were decreased in pigs with high fat skatole levels and low P4502E1 levels (P < .01). The results indicate that oxidation and conjugation reactions of skatole in pig liver have a dramatic effect on skatole levels in the fat. In particular, the formation of F-1 and formation and subsequent sulfation of pro-MII are related to low levels of skatole in the fat, presumably due to rapid metabolic clearance of skatole.

Adipose Tissue↗
PubMed1986

Effects of butylated hydroxyanisole on acetaminophen hepatotoxicity and glucuronidation in vivo.

The present study examined the effects of butylated hydroxyanisole (BHA) on acetaminophen-induced hepatotoxicity and metabolism in vivo with emphasis on possible changes in the glucuronidation pathway. Female Swiss-Webster mice received BHA in the diet (1% w/w) for 12 days (600 to 800 mg/kg/day). BHA prevented acetaminophen hepatotoxicity (600 mg/kg, ip), based on serum alanine and aspartate aminotransferase activities and histopathological examination. The rate of elimination of acetaminophen from blood was 10-fold higher in BHA-fed mice (clearance, 49 ml/min/kg) than in controls (4.4 ml/min/kg). In general, the urinary metabolite excretion patterns in control and BHA-treated mice were the same. However, the rates of acetaminophen conjugation via the sulfation, glucuronidation, and mercapturic acid pathways were enhanced with the rate of glucuronide formation, the major biotransformation pathway of acetaminophen, increased sevenfold in BHA-treated mice (0.041 min-1) compared to controls (0.006 min-1). BHA increased hepatic UDP-glucuronosyltransferase activity twofold, as well as hepatic UDP-glucuronic acid concentrations. In addition, after acetaminophen administration, UDP-glucuronic acid in BHA-treated mice was depleted to a lesser extent and returned to control values more rapidly than in untreated animals. BHA had a similar but less pronounced effect on hepatic glutathione levels. The findings indicate that the rate of acetaminophen glucuronidation is increased in vivo during BHA feeding to mice. This effect appears to play a role in the enhanced excretion of acetaminophen as well as protection against acetaminophen-induced hepatotoxicity.

Acetaminophen↗
PubMed2004

Amino acid residue ILE211 is essential for the enzymatic activity of human UDP-glucuronosyltransferase 1A10 (UGT1A10).

Conjugation of exogenous and endogenous compounds by uridine diphosphoglucuronosyltransferases (UGTs) is a pathway catalyzing the transfer of a glucuronic acid molecule from UDP glucuronic acid to lipophilic aglycones, which become more polar and more easily excretable in the bile or urine. UGTs are divided into two major families, UGT1 and UGT2. The isoform UGT1A10, along with UGT1A7 and UGT1A8, is expressed exclusively in extrahepatic tissues, notably in the gastrointestinal tract. Here, we report the isolation of a mutant clone of the human UGT1A10, at position 211 of the protein, where a threonine residue replaces an isoleucine residue (allele Thr211). Because the isoleucine is conserved among many UGT1A isoforms, we proceeded to the analysis of the activity of the wild-type UGT1A10 (T211I) and compared it with that of the variant enzyme (I211T(*)). In vitro assays with microsomal extracts from stably expressing human embryonic kidney 293 (HEK293) cells showed that the mutant enzyme lost all detectable activity toward major substrates, which demonstrate that the residue isoleucine at position 211 is essential for UGT1A10 activity. Mutant UGT1A10 (I211T(*)) also lost all detectable activity toward mycophenolic acid. Genomic DNA from 103 unrelated individuals was sequenced for this mutation, and two heterozygous genotypes were detected for this mutation (frequency: 2 per 100 individuals). Because UGT1A10 appears to be expressed in all gastrointestinal tissues and is active toward a wide range of substrates, lack of activity of this isoform may have an impact on individual glucuronidation efficiency.

Amino Acid Sequence↗
PubMed2006

Accumulation and metabolism of the anticancer flavonoid 5,7-dimethoxyflavone compared to its unmethylated analog chrysin in the Atlantic killifish.

The use of dietary flavonoids as potential chemopreventive agents is a concept of increasing interest. Recent findings indicate that methylated flavones have the advantage of increased metabolic stability. One such compound, the naturally-occurring 5,7-dimethoxyflavone (5,7-DMF), has been shown to be a potential chemopreventive agent in human cancer originating from the liver, mouth, esophagus and lung. As bioavailability is a key issue for potential in vivo effects, the tissue accumulation and biliary elimination of 5,7-DMF and its non-methylated analog chrysin were examined in a small fish model (Fundulus heteroclitus). The fish were exposed to 5,7-DMF, chrysin or vehicle control (DMSO<0.01%) in seawater for 8h. Toxicity was not observed at the 5microM exposure level. Tissues and bile were harvested and analyzed by HPLC and LC/MS for quantitation and identification of parent compound and metabolites. 5,7-DMF accumulated 20-fold to 100-fold in all tissues examined, with the highest accumulation in liver and brain, whereas chrysin was barely detectable in any tissues except the liver. The bile of chrysin-exposed fish contained very low concentrations of unchanged chrysin but high concentrations of two glucuronic acid conjugates. In the bile of 5,7-DMF-exposed fish, the parent compound was detectable in significant amounts along with glucuronic acid conjugates of O-demethylated 5,7-DMF. In conclusion, our study demonstrated high tissue accumulation and limited metabolism of 5,7-DMF compared to chrysin in vivo, making this flavone a promising chemopreventive molecule.

Animals↗
PubMed1997

Structure of fucose branches in the glycosaminoglycan from the body wall of the sea cucumber Stichopus japonicus.

Fucose-branched chondroitin sulfate E was prepared from the body wall of sea cucumber Stichopus japonicus. The purified glycosaminoglycan (GAG) was chemically desulfated, followed by carboxyl reduction. Intact, desulfated, and desulfated/carboxyl-reduced GAG fractions were subjected to per-O-methylation. GC-MS analyses of the resultant partially methylated alditol acetates demonstrated that the fucose branch is formed by two fucopyranosyl residues linked glycosidically through position (1-->3), and that the fucose branch and glucuronic acid are almost equimolar. In addition, it was elucidated that about 20% of the branches stretch from O-3 position of a glucuronic acid moiety of the core chondroitin sulfate polymer, while remaining fucose branches are postulated to protrude from O-4 and/or O-6 position(s) of a N-acetylgalactosamine moiety. This fucose branch was also confirmed to be highly sulfated according to six kinds of substitution pattern in methylation analysis.

Acetylgalactosamine↗
PubMed2002

[Effect of insulin-like growth factor-I on cultured articular chondrocytes of rabbits].

OBJECTIVE: To investigate the influence of insulin-like growth factor-I (IGF-I) on biological characteristics of articular chondrocytes cultured in vitro of rabbits. METHODS: Monolayer articular chondrocytes of 4-week old rabbits were cultured in medium with IGF-I, at the concentrations of 3, 10, 30, 100, and 300 ng/ml. The DNA content in cells and glucuronic acid content in matrix were detected on the 2nd, 4th, 6th days after culture. RESULTS: The DNA content in cells and the glucuronic acid content in matrix in articular chondrocytes cultured in medium with IGF-I at concentrations of 3-300 ng/ml were all significantly higher than those in control group (P < 0.01), which reached the peak at the concentrations of 30-100 mg/ml on the 4th day. CONCLUSION: IGF-I could obviously promote the proliferation of articular chondrocytes in vitro, and there exist time-dependent and dose-dependent effect.

Animals↗
PubMed2006

Enzymatic and chemical methods for the generation of pure hyaluronan oligosaccharides with both odd and even numbers of monosaccharide units.

Hyaluronan oligosaccharides display physiological activities not associated with the polymer and are widely used to characterize hyaluronan-binding proteins. They can also be used as biocompatible starting blocks for chemical derivatization. Here we present methods for generating milligram quantities of unusual odd- and even-numbered oligosaccharides, greatly increasing the diversity of reagents for use in such studies. These methods are based upon protocols from the 1960s, at which time it was very difficult to assess the stereochemical purity of the products. To address this, products were analyzed with modern high-field nuclear magnetic resonance spectroscopy. Alkaline beta-elimination conditions previously used to remove reducing-terminal N-acetylglucosamine residues in fact introduce a significant ( approximately 30%) level of stereoisomerism in the products by alkali-catalyzed keto-enol tautomerizations. Milder alkaline conditions were used to overcome this problem, reducing the contamination to <5%. The elimination by-products from this reaction were isolated and characterized, allowing the mechanism of alkaline degradation of hyaluronan to be investigated for the first time. beta-Glucuronidase was used to remove nonreducing-terminal glucuronic acid residues from oligosaccharides. Odd-numbered oligosaccharides with terminal glucuronic acid residues isolated from hyaluronidase digests are shown to originate from acid-catalyzed acetal hydrolysis during boiling denaturation and also have significant levels of stereochemical impurities.

Alkalies↗
PubMed1976

[Experimental comparison of the tuberculostatic activities of INH, INHG and INHG-Na (author's transl)].

In a comparative experimental study the glucuronic acid derivatives of isonicotinoylhydrazone (INH), isonicotinoyl-hydrazone d-glucuronic acid lactone (INHG, Gluronazid) and INH-sodium glucuronid (INHG-N-A, Gluronazid pro infusione) were shown to have the same tuberculostatic activity as INH both in vitro and in vivo. As judged by the serum inhibitory activity the serum level shows a different temporal pattern. After the administration of INHG or INHG-Na, the inhibitory activity reaches its peak later than does INH but remains in the active range essentially longer. The most substantial and, with regard to therapy, most significant difference between INHG or INHG-Na and INH lies in the varying toxicological properties. Both the oral and intravenous LD50 increase in the sequence INH, INHG and INHG-Na. The i.v. LD50 of INHG-Na exceeds the oral LD50. As compared to INH the lower toxicity permits a higher dosage of gluronazide. Thus a continuously higher serum inhibitory activity can be achieved than with a corresponding INH therapy.

Administration, Oral↗
PubMed1978

Structure revision of disaccharidic conjugates of bilirubin-IX alpha in human bile and identification of phenylazo derivatives B4, B5, and B6 as 2-, 3- and 4-O-acylglucuronides.

Aniline azopigments B4, B5 and B6, derived from conjugates of bilirubin-IX alpha in human bile, and previously characterized as disaccharidic esters [Kuenzle (1970) Biochem. J. 119, 387-394 and 411-435], were analysed by using t.l.c. and mass spectrometry. The compounds were identified as partially separated mixtures of 2-, 3- and 4-O-acylglucuronide positional isomers. The 1-O-acylglucuronide was not detected in the mixtures and was the only compound hydrolysed with beta-glucuronidase. Further scrutiny of structural assignments made by Kuenzle [(1970) Biochem. J. 119, 411-435] led to identification of the lactone and hexuronic acid derivatives that were obtained from azopigment B5 along with glucuronolactone and glucuronic acid. A branched-chain structure, i.e. 3-C-hydroxy-methyl-D-riburonic acid, was assigned previously, but the derivatives have now been identified as various incompletely silylated forms of glucuronolactone and glucuronic acid. Several trimethylsilyl derivatives glucuronolactone were isolated and characterized by n.m.r. and mass spectrometry.

Azo Compounds↗