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PubMed2006

In vitro inhibitory effects of non-steroidal anti-inflammatory drugs on 4-methylumbelliferone glucuronidation in recombinant human UDP-glucuronosyltransferase 1A9--potent inhibition by niflumic acid.

The inhibitory potencies of non-steroidal anti-inflammatory drugs (NSAIDs) on UDP-glucuronosyltransferase (UGT) 1A9 activity were investigated in recombinant human UGT1A9 using 4-methylumbelliferone (4-MU) as a substrate for glucuronidation. 4-MU glucuronidation (4-MUG) showed Michaelis-Menten kinetics with a Km value of 6.7 microM. The inhibitory effects of the following seven NSAIDs were investigated: acetaminophen, diclofenac, diflunisal, indomethacin, ketoprofen, naproxen and niflumic acid. Niflumic acid had the most potent inhibitory effect on 4-MUG with an IC50 value of 0.0341 microM. The IC50 values of diflunisal, diclofenac and indomethacin were 1.31, 24.2, and 34.1 microM, respectively, while acetaminophen, ketoprofen and naproxen showed less potent inhibition. Niflumic acid, diflunisal, diclofenac and indomethacin inhibited 4-MUG competitively with Ki values of 0.0275, 0.710, 53.3 and 69.9 microM, respectively, being similar to each IC50 value. In conclusion, of the seven NSAIDs investigated, niflumic acid was the most potent inhibitor of recombinant UGT1A9 via 4-MUG in a competitive manner.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2003

Solid-phase peptide synthesis by ion-paired alpha-chymotrypsin in nonaqueous media.

Solid-phase synthesis of dipeptides in low-water media was achieved using AOT ion-paired alpha-chymotrypsin solubilized in organic solvents. Multiple solvents and systematic variation of water activity, a(w), were used to examine the rate of coupling between N-alpha-benzyloxycarbonyl-L-phenylalanine methyl ester (Z-Phe-OMe) and leucine as a function of the reaction medium for both solid-phase and solution-phase reactions. In solution, the observed maximum reaction rate in a given solvent generally correlated with measures of hydrophobicity such as the log of the 1-octanol/water partitioning coefficient (log P) and the Hildebrand solubility parameter. The maximum rate for solution-phase synthesis (13 mmol/h g-enzyme) was obtained in a 90/10 (v/v) isooctane/tetrahydrofuran solvent mixture at an a(w) of 0.30. For the synthesis of dipeptides from solid-phase leucine residues, the highest synthetic rates (0.14-1.3 mmol/h g-enzyme) were confined to solvent environments that fell inside abruptly defined regions of solvent parameter space (e.g., log P > 2.3 and normalized electron acceptance index <0.13). The maximum rate for solid-phase synthesis was obtained in a 90/10 (v/v) isooctane/tetrahydrofuran solvent mixture at an a(w) of 0.14. In 90/10 and 70/30 (v/v) isooctane/tetrahydrofuran environments with a(w) set to 0.14, seven different N-protected dipeptides were synthesized on commercially available Tentagel support with yields of 74-98% in 24 h.

Catalysis↗
PubMed1991

Study of thiol proteases of normal human skin fibroblasts.

The protease activity of cultured normal human skin fibroblasts was studied using the synthetic fluorigenic peptides, the modified protein 4-methylumbelliferyl-casein, the thiol inhibitors and the affinity for concanavalin A-Sepharose. The majority of the activity to N-benzyloxycarbonyl-L-phenylalanyl-L-arginyl-7-amido-4-methyl-coumarin and N-a-benzyloxycarbonyl-L-arginyl-arginyl-7-amido-4-methylcoumarin had a pH optimum of 6.0, and was thiol-dependent and inhibited by leupeptin and antipain. The activity toward N-benzyloxycarbonyl-L-phenylalanyl-L-arginyl-7-amido-4-methylcoumarin represents both cathepsin B and cathepsin L, whereas the activity towards 4-methylumbelliferyl-casein represent only cathepsin L. Cathepsin H could not be detected when assayed with L-arginine-7-amido-4-methylcoumarin substrate. Cathepsin D was present in comparatively small amounts when assayed with 4-methylumbelliferyl-casein. Activity towards 4-methylumbelliferyl-casein had pH optima at 3 and 6 and was stimulated by dithiothreitol. A proportion of the activity at pH 6.0 was not dependent on thiols and not inhibited by leupeptin, and had the general characteristics of a carboxyl proteinase. Over 70 per cent of the activity was in the lysosomal fraction and showed structure-linked latency. All the detectable protein emerged from the immobilized concanavalin A column and the fractions eluted by alpha-methyl-D-mannoside were significantly hydrolysed the synthetic peptides. Only that fraction which bound to concanavalin A was active towards 4-methylumbelliferyl-casein. Cathepsin B had no affinity for concanavalin A-Sepharose due to the absence of glycoprotein content, unlike cathepsin L which showed a strong affinity for concanavalin A-Sepharose.

Caseins↗
PubMed2002

A 45-kDa midgut glycoprotein from Anopheles albimanus mosquito mediates the killing of trypanosomes.

Trypanosomes do not inhabit or grow in anopheles mosquitoes, the vector for the transmission of Plasmodium parasites the causative agent for malaria. The possession of lytic factors by the anopheline mosquito was thus considered. Head and midgut sections prepared in phosphate buffered saline were tested for trypanocidal action against T. congolense. While the head section was inactive towards the trypanosomes, the midgut extract at 0.2 mg ml(-1) diminished the motility of the parasites within 2 min of incubation; killing 50% of the population after 5 min. At 0.5 mg ml(-1) of the extract, about 90% of the parasites were killed within 2 min of incubation. The midgut fraction was subjected to a purification protocol involving successive chromatography on: octyl-sepharose, reactive brown agarose and fetuin-agarose columns. A final trypanocidal active fraction (gp45), which moved homogeneously during electrophoresis as a 45-kDa protein, was recovered from the fetuin-agarose column. The protein reacted positively with thiobarbituric acid, which suggests it is a sialoglycoprotein. Desialylation of the glycoprotein nullified its trypanocidal activity on T. congolense. Similarly, when the saccharides, lactose, methyl-beta-galactoside, lactulose, methyl-umbelliferyl-beta-galactoside (MU-Gal), were included in the culture medium, they inhibited the gp45 trypanocidal activity. Asialo-fetuin and asialo-RBC also inhibited the gp45-induced killing of T. congolense cells. The potential use of anopheline 45 kDa protein in the production of transgenic tsetse flies (Glossina spp.) in the control of trypanosomiasis is discussed.

Animals↗
PubMed1986

Flow cytometric measurement of cytoplasmic pH: a critical evaluation of available fluorochromes.

Three pH-sensitive fluorochromes-4-methyl-umbelliferone(4MU),2, 3-dicyano-hydroquinone (DCH), and 2',7'-bis(carboxyethyl)-5,6-carboxy fluorescein (BCECF)--were evaluated for their resolution, range, and stability of cellular fluorescence. Flow cytometric techniques for determining cytoplasmic pH (pHi) have been fully described for 4MU and DCH; BCECF has previously been used for fluorimetric estimation of pHi, and was adapted to flow cytometry. For each fluorochrome, the ratio of fluorescence intensity at two wavelengths gives a measure of pHi, which may be calibrated by obtaining the fluorescence ratios for cells suspended in buffers of varying pH in the presence of a proton ionophore. Reliable calibration proved difficult using 4MU, partly because of poor retention within cells. Both DCH and BCECF could be calibrated using a fluorescence ratio and had resolutions of 0.2 and 0.4 pH units, respectively. The fluorescence of DCH is so strongly pH dependent that there were practical difficulties in its use over a wide pH range; however, pHi measurements are possible between pH 6.0 and pH 7.5 using either DCH or BCECF. Substantial dye leakage was found for 4MU and, to a lesser extent, DCH, while BCECF was retained by cells for up to 2 hours. Despite its lower resolution BCECF had a usable range of more than 1.5 pH units and this coupled with its stable fluorescence and excitation at 488 nm rather than UV suggests a wide application.

Cell Line↗
PubMed1994

A rapid method for detection of N-acetylglucosaminidase-type chitinase activity in crossed immunoelectrophoresis and sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels using 4-methylumbelliferyl-N-acetyl-D-glucosaminide as substrate.

A method for the detection of N-acetylglucosaminidase (GlcNAcase) activity has been developed by using 4-methyl-umbelliferyl-N-acetyl-D-glucosaminide (4-MU-GlcNAc) as substrate in crossed immunoelectrophoresis (CIE) and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gels. Visualization of the reaction with a 366 nm ultra-violet light is possible in approximately 30 min. The method is fast and sensitive in comparison with previous methods. The same band as in SDS-PAGE, showing both GlcNAcase and chitinase activity, was found in the present study; we therefore conclude that this method is also useful in a GlcNAcase-type chitinase assay.

Acetylglucosamine↗
PubMed1998

Carrier-mediated entry of 4-methylumbelliferyl sulfate: characterization by the multiple-indicator dilution technique in perfused rat liver.

The hepatocellular entry of 4-methylumbelliferyl sulfate (4MUS) a highly ionized and highly bound anion capable of futile cycling, was examined in the single-pass albumin-free perfused rat liver preparation. Desulfation of 4MUS to 4-methylumbelliferone (4MU) was verified in vitro to be a low-affinity, high-capacity process (Km = 731 micromol/L; Vmax = 414 nmol min(-1) g(-1) liver). With 4MUS given to the perfused rat liver, sulfation of 4MU, the formed metabolite, was attenuated in the presence of 2,6-dichloro-4-nitrophenol (DCNP), a sulfation inhibitor, and when sulfate ion was substituted by chloride ion. 4MU sulfation, being a high-affinity system, was reduced most effectively at the lowest 4MUS concentration (15 micromol/L) used, evidenced by the increased (24%) net hepatic extraction ratio of 4MUS and reduced utilization (72%) of infused tracer 35SO4(2-) by 4MU for 4MU35S formation. Single-pass multiple indicator dilution (MID) studies were thus conducted under identical conditions (DCNP and absence of inorganic sulfate), with injection of [3H]4MUS and a set of noneliminated vascular and cellular reference indicators into the portal vein (prograde) or hepatic vein (retrograde), against varying background bulk concentrations of 4MUS (5 to 900 micromol/L). The steady-state removal rate of 4MUS and formation rates of 4MU and its glucuronide conjugate (4MUG) were not altered with perfusion flow direction, suggesting the presence of even or parallel distributions of 4MUS desulfation and 4MU glucuronidation activities. When the outflow dilution profile of [3H]4MUS was evaluated with the barrier-limited model of Goresky, a slight red cell carriage effect was found for 4MUS. The permeability surface area product for cellular entry for prograde showed a dramatic concentration-dependent decrease (from 0.13 to 0.01 mL sec(-1) g(-1), or 7.4 to 0.56 times the blood perfusate flow rate) and was resolved as saturable and nonsaturable components, while data for retrograde were more scattered, varying from 2.8 to 1 times the blood perfusate flow rate. Efflux (coefficient = 0.0096 +/- 0.0024 and 0.0088 +/- 0.0062 mL sec(-1) g(-1), respectively) was relatively insensitive to concentration and flow direction. The same was observed for the removal capacity for metabolism and excretion (sequestration coefficient: for prograde, 0.0056 +/- 0.0017 mL sec(-1) g(-1); for retrograde, 0.0056 +/- 0.003 mL sec(-1) g(-1)). The decrease in the apparent partition coefficient (ratio of 4MUS concentration estimated in tissue to unbound plasma concentration) and the increase in relative throughput component with concentration further substantiate the claim on the presence of concentrative processes at the sinusoidal membrane.

Animals↗
PubMed2003

Aryl sulfatase from Naja nigricolis venom: characterization and possible contribution in the pathology of snake poisoning.

The venom of Naja nigricolis was found to contain a high level of the enzyme aryl sulfatase. The enzyme was isolated from the venom of N. nigriclois and purified to electrophoretic homogeneity by gel chromatography on Sephadex G-100, DEAE-cellulose, and phenyl-sepharose columns. The enzyme was optimally active at pH 5 and 40 degrees C. Arrhenius plot for the determination of the activation energy (E(a)) gave the value 25 kJ/mol with a half-life (t(1/2)) of 5 min at 50 degrees C. It was highly activated by Fe(2+) and Ca(2+) and inhibited by Co(2+) and Mn(2+). The enzyme catalyzed the hydrolysis of the fluorescent compound methylumbelliferyl-sulfate (MU-SO(4)). Double reciprocal plots of initial velocity data, using MU-SO(4) as substrate, gave a K(M) value of 110 microM and V(max) of 225 micromol min(-1) x mg(-1). N. nigricolis Aryl sulphatase also hydrolyzed chondroitin-4-sulphate. It was inhibited competitively by N-acetyl glucosamine sulfate (GlcNAc-SO(4)), glucose-6-sulfate (Glc-6-SO(4)), and glucose 1-sulfate (Glc-1-SO(4)). Extrapolated inhibition binding constants (K(i)) gave the values of 3, 25, and 315 microM for GlcNAc-SO(4), Glc-6-SO(4), and Glc-1-SO(4) respectively.

Acetylglucosamine↗
PubMed1986

Measurement of active phagocytosis by polymorphonuclear leukocytes by fluorescence liberation from phagocytized microspheres.

Phagocytosis by polymorphonuclear leukocytes (PMN) was determined by a newly developed technique based on measurement of liberation of a fluorescence substance from PMN phagosomes; 4-methylumbelliferyl-beta-D-glucuronide (4MUGL), which is a substrate of beta-glucuronidase in lysosome, was conjugated with a microsphere, and 4-methylumbelliferone (4MU) liberated from phagocytized 4MUGL-microspheres was measured. The microspheres were composed of glyceryl-methacrylate having a diameter of 2.0 micron. Liberating activity of six kinds of 4MUGL-microspheres containing various amounts of amino and carboxyl groups was compared. Among these six kinds of 4MUGL-microspheres, four kinds showed activity similar to that of morphological phagocytosis. These four kinds of 4MUGL-microspheres liberated 4MU into the extracellular fluid from PMN during phagocytosis. Furthermore, they were recognized as a substrate of purified beta-glucuronidase. 4MUGL-MS610 showed the highest liberating activity among the four kinds of microspheres. Optimal conditions for phagocytosis by PMN were determined using 4MUGL-MS610. Total liberation of 4MU from the microspheres increased almost linearly with incubation time with PMN from 0 to 60 min and was linear with 4MUGL-MS in concentrations up to 4 X 10(8) microspheres/ml. This liberation was parallel to phagocytosis in a dose-dependent fashion. During 10-min incubation 20.4% of 4MU was liberated from 4MUGL-microspheres with phagocytosis. Seventy-five percent of the liberated 4MU was distributed in the extracellular fluid. 4MU distributed in the extracellular fluid was not attributable to hydrolysis of unphagocytized microspheres by beta-glucuronidase extracellularly leaked from PMN by phagocytosis. Also phagocytized 4MUGL-MS610 by PMN was observed by scanning electron microscopy. These results indicate that 4MU was liberated from 4MUGL-MS by hydrolysis due to beta-glucuronidase released into phagosomes with phagocytosis by PMN. Sensitivity of this assay was limited to about 50 pmol/ml, being less than 0.5-1 microsphere phagocytized into one cell.

Cell Membrane Permeability↗
PubMed1992

The neural cell adhesion molecule (NCAM) heparin binding domain binds to cell surface heparan sulfate proteoglycans.

The neural cell adhesion molecule (NCAM) has been strongly implicated in several aspects of neural development. NCAM mediated adhesion has been proposed to involve a homophilic interaction between NCAMs on adjacent cells. The heparin binding domain (HBD) is an amino acid sequence within NCAM and has been shown to be involved in NCAM mediated adhesion but the relationship of this domain to NCAM segments mediating homophilic adhesion has not been defined. In the present study, a synthetic peptide corresponding to the HBD has been used as a substrate to determine its role in NCAM mediated adhesion. A neural cell line expressing NCAM (B35) and its derived clone which does not express NCAM (B35 clone 3) adhered similarly to plates coated with HBD peptide. A polyclonal antiserum to NCAM inhibited B35 cell-HBD peptide adhesion by only 10%, a value not statistically different from inhibition caused by preimmune serum. Both these experiments suggested no direct NCAM-HBD interactions. To test whether the HBD peptide bound to cell surface heparan sulfate proteoglycans (HSPG), HSPG synthesis was inhibited using beta-D-xyloside. After treatment, B35 cell adhesion to the HBD peptide, but not to control substrates, was significantly decreased. B35 cell adhesion to the HBD peptide could be inhibited by 10(-7) M heparin but not chondroitin sulfate. Preincubation of the substrate (HBD peptide) with heparin caused dramatic reduction of B35 cell-HBD peptide adhesion whereas preincubation of B35 cells with heparin caused only modest reductions in cell-HBD adhesion. Furthermore, inhibition of HSPG sulfation with sodium chlorate also decreased the adhesion of B35 cells to the HBD peptide. These results strongly suggest that, within the assay system, the NCAM HBD does not participate in homophilic interactions but binds to cell surface heparan sulfate proteoglycan. This interaction potentially represents an important mechanism of NCAM adhesion and further supports the view that NCAM has multiple structurally independent binding sites.

Amino Acid Sequence↗
PubMed1988

Membrane-limited hepatic transport of the conjugative metabolites of 4-methylumbelliferone in rats.

The hepatic transports of 4-methylumbelliferone (4-MU) and its conjugative metabolites, the glucuronide (4-MUG) and sulfate (4-MUS), were investigated in rats with various methods. The extraction ratio (E) was estimated with the multiple indicator dilution (MID) method using isolated perfused rat liver. The values of E for 4-MUG and 4-MUS were much lower (less than 0.2) than that for the parent compound, 4-MU (0.89). In addition, we examined the simulation of the outflow curves of conjugates based on the "distributed" model in which we varied the permeability between the blood and hepatocytes. When the permeability was much smaller relative to the hepatic blood flow, the simulated curve was superimposed on the dilution curve. These results suggest that the influx permeabilities of these conjugates are so low that little extraction occurs during the passage through the liver. Measuring the unidirectional uptake of these conjugates into the liver with the in vitro centrifugal filtration method using isolated hepatocytes, we determined the influx permeabilities (PSinf(total] for the total ligands. The value of PSinf(total) determined with the in vitro method was extrapolated to that per gram of liver, assuming 1 g of liver has 1.3 X 10(8) cells. The values of PSinf(total) for 4-MU, 4-MUG, and 4-MUS were 4.8, 0.06, and 0.11 mL/min/g liver, respectively. Thus, the influx permeabilities for 4-MUG and 4-MUS were much smaller than the hepatic blood flow (1.6 mL/min/g liver), confirming the results of MID method.

Animals↗
PubMed1991

Purification and preliminary characterization of guinea pig testicular proteinase inhibitors.

Three guinea pig testicular, low-molecular-weight, acid-stable inhibitors specific for trypsin-like proteinases were isolated, purified, and characterized. The procedure comprised acid extraction of testicular acetone powder, pH precipitation of the extract, gel filtration of the supernatant on Sephadex G-100 and G-50, ion-exchange chromatography on SP-Sephadex, followed by QAE-Sephadex. Final purification was by rechromatography on Sephadex G-50 superfine gel. The three proteinase inhibitors were labeled A, B, and Cnb, the latter to denote nonbinding of Cnb to the QAE-Sephadex. Components A and Cnb showed competitive, whereas B showed noncompetitive, inhibition against trypsin. All three inhibitors were active against trypsin but were ineffective against chymotrypsin. The inhibition constants, Ki, were obtained using trypsin-catalyzed hydrolysis of the N-benzyloxycarbonyl-L-arginyl amide of 7-amino-4-trifluoro-methylcoumarin (CBZ-Arg-AFC) at pH 8.0. The values were calculated to be, for A, 1.5 x 10(-8) M; for B, 1.5 x 10(-8) M; and, for Cnb, 2.2 x 10(-7) M. The Ki values calculated from inhibition of trypsin-catalyzed hydrolysis of the active site titrant 4-methylumbelliferyl-p-guanidinobenzoate (MUGB) using Easson-Stedman plots were, for A, 7.7 x 10(-9) M; for B, 6.7 x 10(-9) M; and, for Cnb, 1.4 x 10(-7) M. The Mrs as determined by active site titration with MUGB were A, 11.2 kDa; B, 10.5 kDa; Cnb, 17.0 kDa. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis gave Mr values for A of 11 kDa, for B of 4 kDa, and for Cnb of 19 kDa. The discrepancy in Mr values for B indicates that it may function as a dimer or trimer in the active state.

Animals↗
PubMed2006

Benign course of glycogen storage disease type IIb in two brothers: nature or nurture?

Two brothers with the childhood variant of type II glycogenosis (GSD-IIb) treated with nutrition and exercise therapy (NET) from a young age showed an unusually benign course. Muscle biopsy from the older brother, which showed characteristic vacuolar glycogen accumulation at age 2, had reverted to normal by age 16. A muscle biopsy from the younger brother was normal at 5 years. It is uncertain whether this anomalous evolution was spontaneous (nature) or due to the symptomatic therapy (nurture), but NET should be considered in patients with GSD-IIb until enzyme replacement or gene therapy become generally available.

DNA↗
PubMed1983

Prenatal diagnosis of cystic fibrosis by methylumbelliferylguanidinobenzoate protease titration in amniotic fluid.

Amniotic fluids were obtained from 19 mothers who had previously given birth to a child with cystic fibrosis. Measurement of methylumbelliferylguanidinobenzoate (MUGB) reactive proteases suggested that all 19 would have unaffected babies. Amongst the first 10 cases to come to term there were 5 infants with cystic fibrosis. It is concluded that MUGB protease titration is not suitable for the early prenatal diagnosis of cystic fibrosis.

Amniotic Fluid↗
PubMed1987

Use of 4-methylumbelliferyl-6-sulpho-2-acetamido-2-deoxy-beta- D-glucopyranoside for prenatal diagnosis of Tay-Sachs disease using chorionic villi.

Prenatal diagnosis of Tay-Sachs disease was performed using the sulphated substrate 4-methylumbelliferyl-6-sulpho-2-acetamido-2-deoxy-beta-D-glucopyranoside to detect hexosaminidase A in chorionic villi. The presence or absence of hexosaminidase A in villi was detected by both a quantitative enzyme assay, and by a rapid, novel procedure which permitted visual discrimination between normal and affected villi.

Chorionic Villi↗
PubMed1994

Prenatal diagnosis of Sanfilippo disease type C using a simple fluorometric enzyme assay.

A new fluorogenic substrate, 4-methylumbelliferyl beta-D-glucosaminide, was used for the assay of acetyl CoA:glucosaminide N-acetyltransferase in chorionic villi, cultured villus cells, and amniocytes. Optimal conditions for the assay and the ranges of enzyme activity were established for the various types of fetal cells. This simple fluorometric assay provides a reliable method for early prenatal diagnosis of Sanfilippo disease type C which is more convenient than current methods using radiolabelled substrates. The method was applied to amniotic fluid cells and fetal fibroblasts from an at-risk pregnancy in which an affected fetus was diagnosed by two-dimensional electrophoresis of glycosaminoglycans in the amniotic fluid.

Acetylglucosamine↗
PubMed1978

Effect of 4-methylumbelliferyl-beta-D-xylopyranoside on the morphology of embryonic cartilage in limb bud cultures.

Limb buds of 11-day-old mouse embryos were cultured for six days in the presence of 0.1, 0.5 or 2 mg/kg 4-methylumbelliferyl-beta-D-xylopyranoside. A dose-dependent decrease in chondrogenesis could be observed in preparations stained with methylene blue and cleared. A reduction or even disappearance (after 2 mg/kg) of intercellular spaces and a change in shape and size of chondroblasts was striking in the light microscopical picture. The electron microscopical findings reveal a decrease in the number, size, and electron-density of the ruthenium-red-positive proteoglycan granules as well as an alteration in the collagen morphology. Up to 1,000 A thick fibrils occur which partly show a so-called continuous cross-striation. In addition, bundles of thin (50-100 A) collagen filaments without cross-striation occur. The number, distribution and packing density of the cell organelles in the chondroblasts are very variable. The vacuoles of the Golgi apparatus are dilated. These effects may be attributed to the xyloside-induced alterations of proteoglycans.

Cartilage↗
PubMed1979

Changes in chemical composition of chick embryos treated with a beta-xyloside and a lathyrogen.

Nine-day chick embryos were treated with 4-methylumbelliferyl beta-D-xyloside or beta-aminopropionitrile fumarate, and their gross chemical composition was examined one week later. Total DNA was 10--20% less in embryos treated with either drug than it was in control embryos. Xyloside-treated embryos showed marked increases in percent wet weight and in sodium/DNA and chloride/DNA ratios, and small decreases in protein/DNA, hydroxyproline/DNA and sulfate/DNA. None of these parameters was affected in embryos treated with beta-aminopropionitrile. Approximately 85% of the uronic acid of control embryos was present as chondroitin sulfate, with a degree of sulfation of 80% and charge density of 1.8; all of this chondroitin sulfate was covalently linked to peptide and had a number-average molecular weight of 29,300. In embryos treated with beta-xyloside, 90% of the uronic acid was present as chondroitin sulfate, with a degree of sulfation of 40% and charge density ranging from 1 to 2; 27% of this chondroitin sulfate, with an average molecular weight of 25,400, was peptide linked, while 73% was linked to 4-methylumbelliferone and had an average molecular weight of 22,900. The chemical differences between embryos treated with the xyloside and embryos treated with the lathyrogen reinforce the conclusion on morphological grounds that these are distinct syndromes involving different aspects of the extracellular matrix.

Abnormalities, Drug-Induced↗