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At least 649 records · Page 36Linked to original sources
PubMed1982

Sulphate and glucuronic acid conjugation of harmol in human fetal and adult liver tissue.

Glucuronidation of harmol in microsomal preparations and sulphate conjugation in hepatic 105,000 g supernatant fractions were studied comparatively in human fetal and adult liver subcellular preparations. The formation of harmol sulphate in the fetal liver was slightly lower than in the adult liver and considerably lower than in rat liver. No glucuronidation of harmol was found in fetal liver, while the activity in adult liver was 30-80 nmol glucuronide formed/2 mg/20 min. In an ontogenic perspective, our in vitro findings are consistent with drug metabolic studies in the human neonate in whom negligible glucuronidation but well-developed sulphate conjugation of paracetamol has been demonstrated.

Adult↗
PubMed1993

Pharmacokinetics and irreversible binding of tolmetin and its glucuronic acid esters in the elderly.

In a previous study, the disposition and irreversible plasma protein binding of tolmetin have been described in young volunteers. Significant levels of tolmetin glucuronide and its isomer(s) were found in plasma, and irreversible binding was shown to occur in all subjects. In the present study, the pharmacokinetics and irreversible binding in 5 elderly volunteers are investigated after a single dose (400 mg) of tolmetin. No difference of physiological importance has been found, unless weight correction is employed, when compared with the young subjects. Very strong correlations were present between the level of binding and exposure to the glucuronide or its isomer. An elderly patient currently treated with tolmetin (400 mg b.i.d.) also participated in the study. The results show an accumulation of the irreversible binding to levels 4-17 times higher than after a single dose. Nevertheless, neither toxic nor allergic reactions have been observed in this patient.

Age Factors↗
PubMed1978

Rearranged glucuronic acid conjugates of bilirubin-IX alpha in post-obstructive bile. Structure elucidation of azopigments beta and gamma as ethyl anthranilate N-glycosides derived from 2-, 3- and 4-o-acyl glucuronides.

Azopigment analysis was performed on conjugates of bilirubin-IXalpha in bile of man and rats obtained after obstruction of the bile duct or in bile incubated under N2. The azopigments beta and gamma, formed by applying a pH 2.7 diazonium reagent containing an excess of ethyl anthranilate, correspond to rearranged ethyl athranilate N-glucuronides having the azodipyrrole acyl group on positions 2, 3 and 4 of the sugar. These assignments were verified, first by conversion of the structurally known 2-, 3- and 4-O-acyl glucuronide azopigments, unsubstituted at C-1, into ethyl anthranilate N-glucuronide reference compounds, and second, by mass spectrometry of trimethylsilyl ether methyl ester derivatives of unknown and reference compounds. The C-1 ethyl anthranilate group of the N-glucuronides triggers characteristics fragmentation reactions of the carbohydrate moiety revealing the position of the azodipyrrole O-acyl group.

Animals↗
PubMed1984

Glucuronic acid conjugation by hepatic microsomal fractions isolated from streptozotocin-induced diabetic rats.

The hepatic glucuronidation of 1-naphthol and 4-nitrophenol (3-methylcholanthrene inducible substrates of glucuronyltransferase, GT 1) was found to be deficient in freshly prepared untreated "native" microsomes from streptozotocin-induced diabetic male rats. The defect was not observed in female rats. Moreover, the glucuronidation of 1-naphthol and 4-nitrophenol was higher in "native" microsomes from male control rats than in those from female controls. This sex difference in the glucuronidation of the GT 1 substrates was abolished by detergent activation of the transferase enzyme in vitro. Streptozotocin treatment did not alter the glucuronidation of paracetamol or phenolphthalein (phenobarbitone inducible substrates for GT 2). This diabetes-induced defect in the glucuronidation of GT 1 substrates was abolished by insulin treatment of the animals and was diminished or completely abolished by detergent activation of the transferase enzyme in vitro. Increased membrane constraint is proposed as the mechanism responsible for the transferase defect. 3-Methylcholanthrene induction abolished the streptozotocin-induced defect in 4-nitrophenol glucuronidation, whereas phenobarbitone did not. This is attributed to the differential effect of these inducers on the microsomal membrane.

Animals↗
PubMed1978

Formation of glucuronic acid conjugates of 7,12-dimethylbenz(a)anthracene phenols in 7,12-dimethylbenz(a)anthracene-treated hamster embryo cell cultures.

Secondary cultures of hamster embryo cells exposed to 0.5 nmol [G-3H]7,12-dimethylbenz(a)anthracene (DMBA) per ml medium metabolized more than 90% of the DMBA within 48 hr. Samples of medium were extracted with chloroform, methanol, and water. The chloroform phases contained about one-third of the DMBA metabolites; the major chloroform-extractable metabolite was 8,9-dihydro-8,9-dihydroxy-7,12-dimethylbenz(a)anthracene. Beta-glucuronidase treatment of the aqueous methanol-soluble metabolites converted almost one-half of them to chloroform-soluble metabolites, of which more than 80% were identified as phenolic derivatives of DMBA. Similar metabolite profiles were obtained by treating the medium with beta-glucuronidase before chloroform extraction. Separation of the methyl group-hydroxylated derivatives of DMBA from the phenolic derivatives was accomplished by high-pressure liquid chromatography. Small amounts of hydroxymethyl derivatives were detected only in the chloroform-extractable material, whereas DMBA phenols were the major component of the beta-glucuronidase-released mateirla. These results indicate that the major pathway of DMBA metabolism in hamster embryo cells is oxidation of the aromatic rings and not oxidation of the methyl groups.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1978

The fate of bilirubin-IXalpha glucuronide in cholestasis and during storage in vitro. Intramolecular rearrangement to positional isomers of glucuronic acid.

1. In aqueous solution above pH7 bilirubin-IXalpha 1-O-acylglucuronide rapidly isomerizes to the non-C-1 glucuronides by sequential migration of the bilirubin acyl group from position 1 to positions 2, 3 and 4 of the sugar moiety. The transformations are enhanced by increasing the pH. Compared with the rates at 37 degrees C the transformations are rather slow at 0 degrees C. Virtually complete inhibition is observed at values below pH6. The isomerization at 25 degrees C and pH 7.4 is not affected by the presence in the solutions of a molar excess of human serum albumin. 2. Isomerization in bile kept at 37 degrees C at pH7.7-7.8 is probably non-enzymic, as the rates of change are similar to those observed under comparable conditions for aqueous solutions of glucuronides of bilirubin-1Xalpha and of azodipyrrole. 3. Analysis without delay of normal biles of man and rats collected at 0 degrees C over a maximum period of 10 min shows that the bilirubin-IXalpha mono- and di-glucuronides consist exclusively of the 1-O-acyl isomers. 4. The mixtures of the four positional isomers of bilirubin-IXalpha glucuronide found in freshly collected biles of man and rats with cholestasis probably originate from initially synthesized 1-O-acylglucuronide by the same mechanism of sequential migration as has been observed in aqueous solutions of conjugated bilirubin-IXalpha.

Animals↗
PubMed1990

Irreversible binding of tolmetin glucuronic acid esters to albumin in vitro.

Tolmetin glucuronide (TG), extracted and purified from human urine, was incubated with albumin in vitro. The degradation profile and irreversible binding to protein were investigated and kinetic parameters calculated. Standard conditions were as follows: TG, 30 micrograms/ml; human serum albumin (HSA), 3%; pH 7.45; 37 degrees C. Lower pH enhanced TG stability and reduced both the extent and the rate of irreversible binding. HSA also increased TG stability, compared to protein-free buffer, but the opposite was observed with bovine serum albumin (BSA). With BSA, irreversible binding was much less, but the rate of adduct formation was the same as with HSA. Essentially fatty acid free HSA behaved similarly to HSA. Preincubation of HSA with warfarin, or diazepam, or an excess of tolmetin, did not influence irreversible binding significantly. In buffer, acyl migration led predominantly to one isomer. This isomer bound irreversibly to HSA, although more slowly and to a lesser extent than the beta 1-isomer. Incubation of TG with poly-L-lysine also resulted in irreversible binding but to a lesser extent than with HSA. Our results suggest that there is more than one binding mechanism, with the preferential pathway a function of the isomers present and the experimental conditions.

Albumins↗