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PubMed1978

Biliary excretion of cyclohexylphenyl 4-[35S]sulphate in the guinea pig.

The metabolic fate and mode of excretion of cyclohexylphenyl 4-[35S]sulphate were studied in the guinea pig. Up to 54.8% of the dose appeared in the bile, the majority as unchanged ester. Substantial amounts of hydroxylated cyclohexylphenyl 4-[35S]sulphate were also excreted in the bile together with minor amounts of the corresponding glucuronic acid conjugate. When isolated guinea-pig livers were perfused with cyclohexylphenyl 4-[35S]sulphate the biliary components were the same as those in the intact animal, although the relative concentration of the hydroxylated derivative was significantly greater. When the hydroxylated derivative was re-injected into guinea pigs it was excreted almost entirely unchanged in the bile. However, in the rat, it was excreted in the bile as a glucuronic acid conjugate. These findings are discussed in relation to studies carried out in the rat [Hearse, Powell, Olavesen & Dodgson (1969) Biochem. Pharmacol. 18, 181--195] and to differences in enzyme activities in rat and guinea-pig liver. The results are also discussed in terms of the molecular-weight threshold for the excretion of anions in guinea-pig bile.

Animals↗

PubMed1995

Characterization of a new class of inhibitors of the recombinant human liver UDP-glucuronosyltransferase, UGT1*6.

The inhibitory effect of a series of novel structurally related compounds on the human UDP-glucuronosyltransferase UGT1*6 stably expressed in a V79 cell line was investigated. The inhibitors contain a lipophilic N-acyl phenylaminoalcohol residue and a uridine moiety connected by a spacer varying for each compound. The effects of these compounds on the glucuronidation reaction measured with 4-methylumbelliferone as substrate were determined. The best inhibitor of the series, D-DPMSU, had an IC50 of 39 microM in the assay conditions. Low Ki values were found toward both UDP-glucuronic acid and 4-methylumbelliferone (17 and 21 microM, respectively). The inhibition was competitive toward both substrates. A similar strong and competitive inhibitory effect was observed with two other inhibitors, DHPASU and DHPASiU. Another compound, D-DPASiU, showed a pure competitive inhibition towards UDP-glucuronic acid, but a non-competitive inhibition towards the acceptor substrate. These data and the optimization of the structures of the inhibitors by molecular modeling suggest that D-DPMSU and DHPASiU compounds may be transition state analog inhibitors of the recombinant UGT1*6 enzyme.

Binding Sites↗

PubMed1989

Isolation, purification, and characterization of fucose-containing sulfated polysaccharides from the brown seaweed Ecklonia kurome and their blood-anticoagulant activities.

A sulfated polysaccharide fraction, obtained from the hot-water extract of the brown seaweed, Ecklonia kurome by removing laminaran and the major part of alginic acid, gave sulfated polysaccharides (B-I, B-II, C-I, and C-II) by both anion-exchange chromatography on a column of Ecteola-cellulose and by fractional precipitation with ethanol containing 0.3% calcium acetate, and then by gel-filtration chromatography on a Sepharose 4B column. B-I and B-II are composed of fucose, galactose, mannose, xylose, glucuronic acid, and ester sulfate in the approximate molar ratios of 1.00:0.36:0.48:1.08:1.85:2.35 and 1.00:0.81:0.18:0.45:0.61:2.00, respectively. C-I and C-II are composed of fucose, galactose, glucuronic acid, and ester sulfate in approximate molar ratios of 1.00:0.03:0.03:1.61 and 1.00:0.19:0.07:1.48, respectively. Blood-anticoagulant activities with respect to activated partial thromboplastin time (APTT) were approximately 24, 19, 81, and 85% of that of heparin for B-I, B-II, C-I, and C-II, respectively. All the polysaccharides showed slight antithrombin activity. No antifactor Xa activity was observed for any of the polysaccharides.

Animals↗

PubMed1966

The synthesis of o-aminophenyl glucuronide in several tissues of the domestic fowl, Gallus gallus, during development.

1. Synthesis of o-aminophenyl glucuronide has been studied in tissues of the domestic fowl, Gallus gallus, during development. 2. The only route of synthesis detected is glucuronyl transfer from UDP-glucuronic acid, and evidence suggests this to be the major pathway. 3. The pathway exists in liver, to a lesser extent in kidney and alimentary tract, and possibly also in skin. It is absent from spleen and adrenal gland. 4. o-Aminophenyl glucuronide formation, UDP-glucuronyltransferase, UDP-glucuronic acid and UDP-glucose dehydrogenase exist in the embryo liver from at least 12 days of incubation. Transferase activity falls just before hatching and rises suddenly on emergence. Overall synthesis of o-aminophenyl glucuronide observed in liver slices confirms this pattern, which also occurs in kidney. UDP-glucuronyltransferase appears in intestinal mucosa only after hatching, and is absent from embryonic spleen. The allantoic membrane forms no o-aminophenyl glucuronide. 5. These findings are related to the isolated existence of an avian embryo.

Adrenal Glands↗

PubMed1993

Anti-complementary acidic polysaccharides from roots of Lithospermum euchromum.

Extremely potent complement activating (anti-complementary) polysaccharides from roots of Lithospermum euchromum were fractionated in a novel way and also assayed for mitogenic and enhancing activity of immune complex binding to macrophages in vitro. Anti-complementary activity and enhancing activity of immune complex binding were observed in the different polysaccharide fractions, but no mitogenic activity was found. The acidic polysaccharide fraction (LR-2) which had the most potent anti-complementary activity was highly heterogeneous, and on further fractionation gave active polysaccharides. Extremely potent anti-complementary polysaccharides, LR-2IId-1a, LR-2IId-1b, LR-2IId-3a and LR-2IId-5a were characterized chemically. These consisted mainly of mannose, galactose, glucose and glucuronic acid, in addition to rhamnose, fucose and arabinose as minor components. Methylation analysis showed that the four polysaccharides contained mainly (1-->3)-linked galactose, (1-->3)-linked fucose and (1-->4)-linked glucose. (1-->3)-Linked mannose was also detected in LR-2IId-1a, 1b and 5a, and (1-->4)-linked glucuronic acid in LR-2IId-1a and 1b as the major glycosidic linkages.

Carbohydrates↗

PubMed2002

Isolation and structure of D-xylans from pericarp seeds of Opuntia ficus-indica prickly pear fruits.

Xylans were isolated from the pericarp of prickly pear seeds of Opuntia ficus-indica (OFI) by alkaline extraction, fractionated by precipitation and purified. Six fractions were obtained and characterized by sugar analysis and NMR spectroscopy. They were assumed to be (4-O-methyl-D-glucurono)-D-xylans, with 4-O-alpha-D-glucopyranosyluronic acid groups linked at C-2 of a (1-->4)-beta-D-xylan. The sugar composition and the 1H and 13C NMR spectra showed that their chemical structures were very similar, but with different proportions of D-Xyl and 4-O-Me-D-GlcA. Our results showed that, on average, the water soluble xylans have one nonreducing terminal residue of 4-O-methyl-D-glucuronic acid for every 11 to 14 xylose units, whereas in the water non-soluble xylans, xylose units can varied from 18 to 65 residues for one nonreducing terminal residue of 4-O-methyl-D-glucuronic acid.

Magnetic Resonance Spectroscopy↗

PubMed1980

The metabolism of 7-ethoxycoumarin in primary maintenance cultures of adult rat hepatocytes.

7-Ethoxycoumarin is metabolized to 7-hydroxycoumarin in short-term (1-4 days) maintenance cultures of adult rat hepatocytes. The 7-hydroxycoumarin is predominantly found as the sulphate and glucuronic acid conjugates. This pattern of metabolism is very similar to that observed with freshly-isolated rat hepatocytes and suggests that the culture system may be of value in studying the metabolism of novel chemicals designed for human therapeutic use. The specific activity of microsomal monooxygenase activity falls by 50-60% during 4 days in culture. This is not reflected by the sulphate and glucuronic acid conjugation pathways which are retained at normal levels throughout the entire 4-day culture period.

Animals↗

PubMed1994

Antitumor activities and immunochemical properties of the cell-wall polysaccharides from Aureobasidium pullulans.

Delipidated cell walls from Aureobasidium pullulans were fractionated systematically. The cell surface heteropolysaccharide contains D-mannose, D-galactose, D-glucose, and D-glucuronic acid (ratio, 8.5:3.9:1.0:1.0). It consists of a backbone of (1-->6)-alpha-linked D-mannose residues, some of which are substituted at 0-3 with single or beta-(1-->6)-linked D-galactofuranosyl side chains, some terminated with a D-glucuronic acid residue, and also with single residues of D-glucopyranose, D-galactopyranose, and D-mannopyranose. This glucurono-gluco-galactomannan interacted with antiserum against Elsinoe leucospila, which also reacted with its galactomannan, indicating that both polysaccharides contain a common epitope, i.e., at least terminal beta-galactofuranosyl groups and also possibly internal beta-(1-->6)-linked galactofuranose residues. It was further separated by DEAE-Sephacel column chromatography to gluco-galactomannan and glucurono-gluco-galactomannan. The alkali-extracted beta-D-glucan was purified by DEAE-cellulose chromatography to afford two antitumor-active (1-->3)-beta-D-glucans. One of the glucans (M(r), 1-2 x 10(5)) was a O-6-branched (1-->3)-beta-D-glucan with a single beta-D-glucosyl residue, d.b., 1/7, and the other (M(r), 3.5-4.5 x 10(5)) had similar branched structure, but having d.b., 1/5. Side chains of both glucans contain small proportions of beta-(1-->6)- and beta-(1-->4)-D-glucosidic linkages.

Antineoplastic Agents↗

PubMed1992

Chondroitin sulfate in the extracellular matrix of the medial and lateral superior olivary nuclei in the dog.

Chondroitin sulfate was examined in the extracellular matrix of the canine medial and lateral superior olivary nuclei by light and electron microscopic immunocytochemistry. The extracellular matrix around the large neurons was intensely stained with a monoclonal antibody recognizing D-glucuronic acid 2-sulfate----N-acetylgalactosamine 6-sulfate (D-unit) and this staining degree was remarkably reduced after chondroitinase ABC digestion. Neuronal cytoplasm, glial cells or capillaries in these nuclei were not stained with the monoclonal antibody. The results indicate the presence of disaccharide residue of D-glucuronic acid 2-sulfate----N-acetylgalactosamine 6-sulfate in the chondroitin sulfate proteoglycan of the extracellular matrix.

Animals↗

PubMed1999

Identification of glucoside and carboxyl-linked glucuronide conjugates of mycophenolic acid in plasma of transplant recipients treated with mycophenolate mofetil.

1. Mycophenolic acid (MPA), is primarily metabolized in the liver to 7-O-MPA-beta-glucuronide (MPAG). Using RP-h.p.l.c. we observed three further MPA metabolites, M-1, M-2, M-3, in plasma of transplant recipients on MMF therapy. To obtain information on the structure and source of these metabolites: (A) h.p.l.c. fractions containing either metabolite or MPA were collected and analysed by tandem mass spectrometry; (B) the metabolism of MPA was studied in human liver microsomes in the presence of UDP-glucuronic acid, UDP-glucose or NADPH; (C) hydrolysis of metabolites was investigated using beta-glucosidase, beta-glucuronidase or NaOH; (D) cross-reactivity of each metabolite was tested in an immunoassay for MPA (EMIT). 2. Mass spectrometry of M-1, M-2, MPA and MPAG in the negative ion mode revealed molecular ions of m/z 481, m/z 495, m/z 319 and m/z 495 respectively. 3. Incubation of microsomes with MPA and UDP-glucose produced M-1, with MPA and UDP-glucuronic acid MPAG and M-2 were formed, while with MPA and NADPH, M-3 was observed. 4. Beta-Glucosidase hydrolysed M-1 completely. Beta-Glucuronidase treatment led to a complete disappearance of MPAG whereas the amount of M-2 was reduced by approximately 30%. Only M-2 was labile to alkaline treatment. 5. M-2 and MPA but not M-1 and MPAG cross-reacted in the EMIT assay. 6. These results suggest that: (i) M-1 is the 7-OH glucose conjugate of MPA; (ii) M-2 is the acyl glucuronide conjugate of MPA; (iii) M-3 is derived from the hepatic CYP450 system.

Chromatography, High Pressure Liquid↗

PubMed1986

Expression of glutathione S-transferase and phenol sulfotransferase, but not of UDP-glucuronosyltransferase, in the human lung tumor cell lines NCI-H322 and NCI-H358.

The expression of xenobiotic-metabolizing enzymes was studied in the human lung tumour cell lines NCI-H322 and NCI-H358. These cells are derived from adenocarcinomas and exhibit features of Clara cells and alveolar type II cells, respectively. Examination of the in vitro activities showed that both cell lines lack UDP-glucuronosyltransferase against the substrates 3-hydroxybenzo[a]pyrene (3-OH-BaP) and 4-hydroxybiphenyl (4-OH-Bph) and that in vitro conjugation of sulfate with 3-OH-BaP was only just detectable. In contrast, both cell lines showed fairly high levels of glutathione-S transferase activity with the substrate 1-chloro-2,4-dinitro-benzene (54.4 and 83.0 nmol/min X mg protein, respectively) and of glutathione (81 and 41 nmole/mg protein, respectively). The metabolic capacity of intact NCI-H322 and NCI-H358 cells was examined using benzo[a]pyrene (BaP) and 3-OH-BaP as substrates. The cell lines formed sulfate conjugates from 3-OH-BaP (4.5 and 0.4 pmol/min X mg protein, respectively) but did not produce any detectable glucuronides. When cultures of the two cell lines were exposed to BaP, phenolic products accumulated in the growth medium. NCI-H322 cells also formed some sulfate conjugates, whereas such conjugates were barely detectable in the medium of NCI-H358 cells. In contrast A549, a human pulmonary adenocarcinoma cell line known to contain UDP-glucuronosyltransferase activity, efficiently conjugated 3-OH-BaP to glucuronic acid and converted the primary phenolic products formed from BaP to glucuronides. Thus the NCI-H322 and NCI-H358 cells are exceptional in that they possess no or very little glucuronosyltransferase activity but exhibit appreciable monooxygenase activity. The cell lines may therefore be of interest for examining the biological effects of potentially toxic chemicals which are otherwise detoxified by glucuronic acid conjugation. The cells may also be useful as test systems for evaluating the potential cytotoxicity and genotoxicity of chemicals to human lung.

Arylsulfotransferase↗

PubMed1995

Polysaccharides from the seeds of Senna multijuga.

The seeds of Senna multijuga were extracted with water or 1% acetic acid and treated with ethanol, resulting in two insoluble fractions. After purification, the major one (FIA, 23%) was shown to be a galactomannan (Man:Gal 2.3:1; [alpha] = +54.6; [eta] = 1340 ml g-1). It consists of a main chain of (1-->4)-linked beta-D-mannopyranosyl residues substituted at O6 by single-unit alpha-D-galactopyranosyl side chains. The second fraction (FIB, 2.5%) was an O-acetyl-glucuronoarabinoxylan from the seed coats (O-acetyl 8.3 mol%; glucuronic acid 11.7%, Xyl:Ara ratio 20:1), which showed a predominance of 4-O-substituted Xylp units (84.4%), branched at O3 with non-reducing end units of Xylp, Araf and glucuronic acid. The O-acetyl positions in D-xylosyl units are at O2 (4.8%), O3 (4.4%) and O2,3 (0.9%). The ratio between O3 and O2 determined by 13C-nuclear magnetic resonance spectroscopy is 1.5:1.

Acetates↗

PubMed1985

Formation of benzo[a]pyrene-3,6-quinol mono- and diglucuronides in rat liver microsomes.

The formation of benzo[a]pyrene (BP)-3,6 quinol glucuronides in liver microsomes in the presence of UDP-glucuronic acid and NAD(P)H appears to occur by a sequence of three reactions: BP-3,6-quinone----BP-3,6 hydroquinone----BP-3,6-quinol monoglucuronide----BP-3,6-quinol diglucuronide. This conclusion is based on the following results. Incubations with [14C]BP-3,6-quinone or UDP-[14C]glucuronic acid and analysis of the samples by TLC established the existence and identity of the two BP-3,6-quinol glucuronides which exhibit different fluorescence spectra. The nature of the monoglucuronide, i.e., a quinol and not a semiquinone glucuronide, was suggested by the finding that the rate of diglucuronide formation was the same with or without NAD(P)H provided that a sufficient amount of monoglucuronide had been formed prior to oxidation of the nucleotides. Furthermore, BP-3,6-quinol monoglucuronides can serve as substrates in the formation of diglucuronides. The ratio between the decrease in monoglucuronides and the formation of diglucuronides was found to be close to 1, suggesting that the conversion of the monoglucuronide of BP-3,6-quinol to the diglucuronide is also catalyzed by UDP-glucuronosyltransferase. However, great differences in the pattern of induction of mono- and diglucuronide formation indicate that two different UDP-glucuronosyltransferases are involved. The yield of BP-3,6-quinol glucuronides with NADH relative to NADPH and the increase in glucuronide formation observed in the presence of cytosolic DT-diaphorase (NAD(P)H-quinone oxidoreductase) are discussed with regards as to whether DT-diaphorase plays an important role as a BP-3,6-quinone reductase in the formation of BP-3,6-quinol glucuronides compared to other NAD(P)H-oxidizing flavoproteins.

Animals↗

PubMed1989

Host-range related structural features of the acidic extracellular polysaccharides of Rhizobium trifolii and Rhizobium leguminosarum.

Proton nuclear magnetic resonance (1H NMR) and fast atom bombardment mass spectrometric analyses were performed on enzymatically derived oligosaccharides from the acidic excreted polysaccharides (EPS) from representative bacterial strains of the pea-nodulating symbiont, Rhizobium leguminosarum (128C53, 128C63, and 300) and the clover-nodulating symbiont, Rhizobium trifolii (NA-30, ANU843, 0403, TA-1, LPR5035, USDA20.102, and 4S). The results revealed structural similarities and differences between EPS of these two species. Octasaccharide units containing galactose, glucuronic acid, alpha-L-threo-hex-4-enopyranosyluronic acid, and glucose in a molar ratio of 1:1:1:5 were obtained from the EPS of the three R. leguminosarum strains and had the same primary glycosyl sequence and location of pyruvate, acetate, and 3-hydroxybutyrate substituents. About 80% of the galactose residues were acylated with 3-hydroxybutyrate, and there were two acetyl groups per repeating unit distributed between the 2 glucose residues of the main chain-derived sequence of the octasaccharides. In contrast, the R. trifolii strains had varied EPS structures, each of which differed from the common R. leguminosarum EPS structure. The EPS from one group of R. trifolii strains (0403 and LPR5035) most closely resembled the R. leguminosarum EPS but differed in that a lower number of galactose and glucose residues were substituted by 3-hydroxybutyryl and acetyl groups, respectively. The EPS from a second group of R. trifolii strains (ANU843, TA-1, and NA-30) was even more different than the R. leguminosarum EPS. These R. trifolii octasaccharides bore a single acetyl group on O-3 of the glucuronic acid residue. In addition, the level of acylation by 3-hydroxybutyryl groups was 50% of that present in the R. leguminosarum EPS. The remaining two strains of R. trifolii (USDA20.102 and 4S) had very different patterns of acylation to each other and to all of the other strains. The EPS from strain USDA20.102 practically lacked 3-hydroxybutyryl groups and had a unique degree and pattern of acetylation. The oligomers from the EPS of R. trifolii strain 4S completely lacked 3-hydroxybutyryl groups and galactose. The latter EPS contained only one O-1-carboxyethylidene group and had a different degree and pattern of acetylation. Interestingly, these two latter strains differ from the other R. trifolii strains in nodulation rates on rare clover species in the Trifolium cross-inoculation group. Thus, we define several groups of R. trifolii based upon their EPS structures and establish their similarities and distinct differences with the EPS of R. leguminosarum.(ABSTRACT TRUNCATED AT 400 WORDS)

Gas Chromatography-Mass Spectrometry↗

PubMed1976

[Immunological demonstration of beta-glucuronidase in eccrine sweat (author's transl)].

Electrophoretic and immunological investigations on highly concentrated sweat have shown that human eccrine sweat contains 6 different esterases. Two of them were found to hydrolyze naphthol-AS-Bi-beta-D-glucuronide. One of the two glucuronic acid ester splitting enzymes is likely to be a substrate-specific beta-glucuronidase. The other one is a non-specific carboxyl-esterase occurring in numerous organs and glandular secretions. This non-specific enzyme of widespread distribution can be mistaken for beta-glucuronidase because it hydrolyzes glucuronic acid esters as well as other synthetic substrates.

Carboxylic Ester Hydrolases↗

PubMed1984

Metabolism of benzo[a]pyrene by cultured human hepatocytes from multiple donors.

Primary hepatocyte cultures from six human donors were established and their abilities to metabolize the polycyclic aromatic hydrocarbon carcinogen benzo[a]pyrene (B[a]P) were examined. Cells from each donor were plated at similar densities (1 X 10(7) cells/100 mm dish). All cultures metabolized B[a]P to a significant extent (24-35 nmol in 24 h) and h.p.l.c. profiles of the organic solvent-soluble and glucuronidated B[a]P metabolites were obtained for all donors. The predominant extracellular organic solvent-soluble B[a]P metabolites were the 9,10- and 7,8-dihydrodiols, 9-hydroxy-B[a]P, and a mixture of tetrols, but the general ratios of these metabolites varied widely among the cells from different donors. In contrast, profiles were highly reproducible in cells from the same donor treated with B[a]P at either 8 or 24 h after initial plating. There was less variability in the amounts of specific B[a]P metabolites conjugated to glucuronic acid by cells from various donors. This variability could not be correlated with cell viability or overall levels of B[a]P metabolism. In addition, B[a]P metabolism by fresh and cryopreserved hepatocytes from the same donor was compared. While there was only a small reduction in the level of total B[a]P metabolism after cell freezing, there was a 3- to 5-fold increase in production of B[a]P-7,8-dihydrodiol, found both in the extracellular medium and as glucuronic acid conjugates, by the cryopreserved cells tested.

Adolescent↗

PubMed1997

High levels of (24S)-24-hydroxycholesterol 3-sulfate, 24-glucuronide in the serum and urine of children with severe cholestatic liver disease.

Extracts of urine and serum from children with cholestatic liver disease were analyzed by fast atom bombardment (FAB) mass spectrometry. About half of all spectra showed a peak at m/z 657, compatible with the presence of a glucuronidated cholestenediol sulfate. Separation by ion exchange chromatography before and after solvolysis and treatment with beta-glucuronidase, combined with analyses by gas chromatography-mass spectrometry and FAB mass spectrometry with collision-induced dissociation, showed that the major compound responsible for the peak at m/z 657 was (24S)-24-hydroxycholesterol 3-sulfate, 24-glucuronide. The double conjugate of 27-hydroxycholesterol was also identified and double conjugates of cholestene- and cholestanetriols were also present. Semiquantitative analyses of the double conjugate of 24-hydroxycholesterol in patients whose FAB spectra showed a peak at m/z 657 indicated serum levels of 2-18 microM and a daily urinary excretion of 0.1-2.7 mumol/24 h. Eleven of 13 studied patients with a prominent peak at m/z 657 in the FAB spectra of their serum or urine either underwent liver transplantation or died. It is concluded that double conjugation of hydroxysterols with sulfuric and glucuronic acids can be an important metabolic pathway, particularly for (24S)-24-hydroxycholesterol. It is speculated that serious cholestatic liver disease may induce an increased formation and release of (24S)-24-hydroxycholesterol from brain (Lütjohann et al. 1996, Proc. Nutl. Acad. Sci. USA. 93: 9799-9804) with subsequent extracerebral conjugation with sulfuric and glucuronic acids.

Biomarkers↗

PubMed1984

Urinary D-glucaric acid excretion during rifampicin/isoniazid and anticonvulsant enzyme induction.

As measured by urinary D-glucaric acid excretion, an index of hepatic enzyme induction, glutethimide was the most powerful of six such inducers tested. In patients with tuberculosis, rifampicin, 450 mg daily, induced excretion rates of the lower dose range of anticonvulsants in epileptics. The effect was detectable in the first few days but the degree and rate of rise to maximum excretion were variable. This may be due either to disposition of rifampicin or to genetic susceptibility to enzyme induction. Plasma beta-glucuronidase, an essential enzyme of the glucuronic acid pathway, could be induced independently of an increase in D-glucaric acid excretion. Plasma gamma-glutamyltranspeptidase-levels, an index of hepatic microsomal enzyme induction, were elevated in only 20 of 83 subjects receiving rifampicin and isoniazid, and in all of them urinary D-glucaric acid excretion was normal. Neither of these indices, therefore, showed hepatic enzyme induction during combined therapy when other pathways such as oxidative metabolism continued to be induced. Different active sites of rifampicin and isoniazid on glucuronic acid and other biochemical pathways emphasize the complexity of final metabolic effects in patients on long-term therapy.

Adolescent↗