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Query: UNIPROT:P06889 (Mol)
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The nephropathy induced by mercuric chloride was assessed in unilaterally nephrectomized (NPX) and sham-operated (SO) rats using histological and urinalysis techniques. This assessment was carried out in order to test whether or not rats are more susceptible to the nephrotoxic effects of mercuric chloride after unilateral nephrectomy and a period allowing for compensatory renal growth. Twelve days after surgery both NPX and SO rats were given a single 1.5, 2.0 or 2.5 mumol/kg dose of mercuric chloride (i.v.). Twenty-four hours after the 1.5 or 2.0 mumol/kg dose of mercuric chloride was administered, cellular and tubular necrosis in the pars recta segments of proximal tubules in the outer medulla was more severe in NPX rats than in SO rats. Moreover, the urinary excretion of a number of cellular enzymes (e.g. lactate dehydrogenase) and plasma solutes (e.g. albumin) was greater in NPX rats than in SO rats. At the 2.5 mumol/kg dose of mercuric chloride, renal tubular damage was quite extensive in both groups of rats; to such an extent that possible differences in renal tubular damage between the NPX and SO rats could not be determined histologically. However, the urinary excretion of alanine aminopeptidase was greater in the NPX rats than in the SO rats. Therefore, based on the aforementioned findings, rats that have undergone and adapted to a reduction in renal mass (i.e. unilateral nephrectomy) appear to be more vulnerable to the nephrotoxic effects of mercuric chloride than rats with two normal kidneys.
Virchows Arch B Cell Pathol Incl Mol Pathol 1987
PMID:Mercuric chloride-induced nephrotoxicity in the rat following unilateral nephrectomy and compensatory renal growth. 289 Dec 17

The expression of the mRNA for mouse testicular lactate dehydrogenase (LDH-X) was examined by RNA:cDNA hybridization in situ in the testis and by Northern analyses of meiotic and postmeiotic spermatogenic cell populations. Silver grains accumulated in cells inside the second layer from the periphery of the seminiferous tubule, confirming previous findings that LDH-X mRNA first appears in the spermatocyte and continues to accumulate until the late spermatid stage. Northern analyses showed that meiotic and postmeiotic cells contained 1.2 and 1.3 kb classes of hybridizing mRNA, respectively. RNase H digestion of oligo (dT)-hybridized RNA and poly(U)-Sepharose column chromatography with differential elution by formamide revealed that the difference in size of the two classes of mRNAs was due to the poly(A) tail length of the LDH-X mRNA. When the distribution of the LDH-X mRNA was examined across polysome gradients, both mRNAs were partially associated with polysomes. These results suggest that the changes in the polyadenylation of LDH-X mRNA were associated with the meiotic division during spermatogenesis in the mouse. They raise the possibility that the stable accumulation of the LDH-X mRNAs in the postmeiotic cells is enhanced by poly(A) tails of increased length.
Mol Reprod Dev 1988
PMID:Changes in polyadenylation of lactate dehydrogenase-X mRNA during spermatogenesis in mice. 290 41

Vertical starch gel electrophoresis was used to resolve proteins encoded by 18 gene loci in ascaridoid nematodes. Estimates of genetic variability were made from population samples of the dog ascarid (Toxocara canis), cat ascarid (Toxocara cati), and the horse ascarid (Parascaris equorum). Levels of polymorphism and mean heterozygosity were high, which is not consistent with the hypothesis that the intestinal environment selects for monomorphism among endoparasites. Most observed allele frequencies conformed to Hardy-Weinberg equilibrium expectations as tested by chi2 goodness-of-fit, suggesting that the proteins evaluated are inherited in a Mendelian fashion and that these nematodes are mating at random. Subunit structures of the following enzymes, deduced from electrophoretic phenotypes of heterozygotes, corresponded to those of vertebrates: lactate dehydrogenase; malate dehydrogenase; 6-phosphogluconate dehydrogenase; phosphoglucomutase; esterase D; peptidase B; peptidase D; and mannose-6-phosphate isomerase. This observation substantiates the conservative nature of polypeptide subunit number across phylogenetically diverse groups of organisms.
Mol Biochem Parasitol 1986 Jan
PMID:Biochemical polymorphism in Parascaris equorum, Toxocara canis and Toxocara cati. 293 2

The purpose of this study was to determine whether thyroid hormone could directly affect the phenotypic expression of two isozymic systems [lactate dehydrogenase (LDH) and myosin] and the energy transducing potential of cultured neonatal heart cells. In addition we determined if these biochemical systems developed in culture as they normally do during in vivo post-natal development. Cells were maintained for 14 days in culture medium containing 10% horse serum and Earle's salts. Experimental cultures were supplemented with 10 nmol/l 3,3',5-triiodo-L-thyronine (T3). Hearts used to study in vivo development were excised from rats at the ages of 2 and 14 days post-natal to correspond with the time of isolating and harvesting the cultured heart cells, respectively. Adult hearts were used to represent the final developmental stage. Cultured cardiomyocytes without T3 administered to the culture medium showed no change in the isozymic profiles (myosin and LDH) or in metabolic potential during the 2 week culture period. The T3 treated cultures showed a complete shift to the V1 myosin isozyme. The glycolytic and aerobic metabolic potential [i.e., phosphofructokinase (PFK) and citrate synthase (CS) activities] and the LDH isozyme distribution were unaltered by T3 treatment. During in vivo development a shift toward the V1 myosin and H-LDH isozymes along with an increase in aerobic metabolism occurred in the rat heart. These findings indicate that the development of these selected biochemical systems in cultured cardiac myocytes does not result from an intrinsic myogenetic program and thus must be regulated in vivo by epigenetic factor(s). These results show that T3 has the potential to be the prime determinant of the phenotypic expression of the myosin isoforms, but does not have the potential to be the sole determinant for the expression of the LDH isozymes or the glycolytic (PFK) and aerobic (CS) capacities of cardiac muscle cells.
J Mol Cell Cardiol 1988 Aug
PMID:The effects of triiodothyronine on cultured neonatal rat cardiac myocytes. 297 10

As a first step in studies of the molecular mechanism(s) underlying gentamicin toxicity, rat kidney cortex has been subfractionated using differential centrifugation. An analytical, rather than preparative approach was used. DNA was used as a marker for the nuclei, cytochrome oxidase for mitochondria, acid phosphatase for lysosomes, catalase for peroxisomes, NADPH-cytochrome c reductase for the endoplasmic reticulum, p-nitrophenyl-alpha-mannosidase (at pH 5.5) for the Golgi apparatus, AMPase for the plasma membrane in general, and alkaline phosphatase for the brush border, and lactate dehydrogenase for the cytosol. In addition, electron microscopy was performed on the subfractions obtained. The distributions of subcellular markers obtained here for the rat kidney cortex closely resemble the corresponding distributions reported for rat liver. This procedure can now be used to look for biochemical and/or toxic changes which might be reflected in an altered distribution pattern for marker enzymes.
Exp Mol Pathol 1987 Apr
PMID:Biochemical effects of gentamicin on rat kidney cortex. I. Analytical subfractionation of control tissue. 303 Jul 99

As a first step in studies on the molecular mechanism(s) underlying gentamicin toxicity, the effect of treating rats with this aminoglycoside antibiotic (100 mg/kg once or twice daily for 3 days) on the analytical subfractionation of the kidney cortex has been examined. DNA was used as a marker for the nuclei, cytochrome oxidase for mitochondria, acid phosphatase for lysosomes, catalase for peroxisomes (with reservations; see the companion paper), NADPH-cytochrome c reductase for the endoplasmic reticulum, p-nitrophenyl-alpha-mannosidase (at pH 5.5) for the Golgi apparatus, AMPase for the plasma membrane in general and alkaline phosphatase for the brush border, and lactate dehydrogenase for the cytosol. In addition, the presumptive lysosomal hydrolases N-acetyl-beta-D-glucosaminidase, p-nitrophenyl-alpha-mannosidase (at pH 4.5), cathepsin D, and DNase II were monitored. Electron microscopy was also performed on the subfractions obtained. The only significant biochemical changes brought about by gentamicin treatment were that N-acetyl-beta-D-glucosaminidase demonstrated both a greater total activity and a larger enrichment in the 104,000gav pellet, while p-nitrophenyl-alpha-mannosidase at pH 4.5 demonstrated the same total activity and a greater enrichment in the 104,000gav pellet. Since myeloid bodies were shown by electron microscopy to sediment primarily with the 500gav and 10,000gav pellets, the biochemical changes seen cannot be associated with these morphological structures. These findings suggest that selective changes in a certain subpopulation(s) of lysosomes or in certain lysosomal enzymes may be involved in the early stages of gentamicin toxicity. On the other hand, no lysosomal membrane damage was observed here, since both the latency of acid phosphatase and the recovery of this activity in the soluble cytosol were unchanged. The present investigation may also have relevance for the dosage and duration of gentamicin treatment chosen in clinical situations.
Exp Mol Pathol 1987 Apr
PMID:Biochemical effects of gentamicin on rat kidney cortex. II. Analytical subfractionation after short-term, high-dose treatment. 303 Aug

Bacillus stearothermophilus lactate dehydrogenase was purified from an overexpressing Escherichia coli cell line. The enzyme has been crystallized in several different forms. All of these crystal forms were grown in the presence of NADH, sodium oxamate and fructose 1,6-bisphosphate. Three crystal forms have been characterized, an orthorhombic P2(1)2(1)2 (type III, a = 86 A, b = 105 A, c = 136 A) and two monoclinic P21 forms (type IV, a = 85 A, b = 118 A, c = 136 A, beta = 96 degrees; type V, a = 112 A, b = 85 A, c = 136 A, beta = 91 degrees). Precession photographs from these crystal forms are very alike, suggesting the molecular packing to be similar in all three forms. The P21 type IV crystals diffract to beyond 2 A spacing and are stable to irradiation with X-rays. A complete medium-resolution (4.7 A) dataset has been collected from a single crystal using synchrotron radiation. Rotation function studies with these data show the two tetramers of the asymmetric unit to be in very similar orientations. Higher-resolution data are being collected.
J Mol Biol 1988 Dec 20
PMID:Crystallization of a ternary complex of lactate dehydrogenase from Bacillus stearothermophilus. 306 14

Primary monolayer cultures of adult rat hepatocytes exposed to the hepatocarcinogen aflatoxin B1 (AFB1) undergo a characteristic prelethal cytomorphological change that is distinct from their response to the necrogenic noncarcinogenic hepatotoxin, acetaminophen (AAP). Since changes in cell shape are mediated, at least in part, by the F-actin cytoskeleton, we designed experiments to study early prelethal alterations in the distribution of actin microfilaments in monolayer rat hepatocytes exposed to AFB1 (100 microM) or AAP (16 mM). Using rhodamine-phalloidin fluorescence microscopy, we observed that normal hepatocytes showed a submembranous F-actin distribution with focal short microfilaments extending into filopodia along the periphery of the cell. Hepatocytes exposed to AFB1 for several hours exhibited retraction of their cytoplasm within a prominent circumferential peripheral band of F-actin microfilament bundles. Retraction of focal areas of peripheral cytoplasm was associated with an increased prominence of the radial F-actin-containing filopodia. Subsequently, there appeared peripheral blebs containing very little F-actin. Hepatocytes exposed to equivalently lethal concentrations of AAP initially remained structurally normal. After several hours, the cells exhibited a prominent polar aggregate of short microfilament bundles without the formation of blebs. Both the blebbing and the polar aggregation of F-actin bundles occurred prior to cell death as shown by lactate dehydrogenase release and trypan blue exclusion. These studies support the hypothesis that the lethal effects of these two agents may occur by different biological mechanisms that are associated with remarkably distinct prelethal cytoskeletal responses.
Exp Mol Pathol 1987 Aug
PMID:Aflatoxin B1 and acetaminophen induce different cytoskeletal responses during prelethal hepatocyte injury. 311 78

The effects of retinol and retinoic acid on unscheduled DNA synthesis (UDS) in primary Sprague-Dawley rat hepatocytes were studied in the presence and absence of known chemical and physical mutagens. Neither retinol nor retinoic acid caused a significant increase in UDS over solvent control at concentrations ranging from 1 microM to 50 microM. Retinol and retinoic acid did not significantly affect 200 micrograms/mL ethyl methanesulfonate(EMS)- or 32 J/m2 ultraviolet light(UV)-induced UDS at concentrations ranging from 1 microM to 50 microM. In contrast, retinol and retinoic acid significantly inhibited 2.5 micrograms/mL and 5.0 micrograms/mL 7,12-dimethyl-benz[a]anthracene(DMBA)-induced UDS at concentrations of 1 microM or greater. Retinol- and retinoic acid-induced hepatocytotoxicity was studied in vitro using lactate dehydrogenase (LDH) release as an indicator of cytoxicity. Neither retinol nor retinoic acid caused significant increases in LDH release over solvent control 3 hours after treatment, whereas retinol caused a biologically significant increase in LDH release 24 hours posttreatment at concentrations of 50 microM and 100 microM. These data suggest that nontoxic concentrations of retinol and retinoic acid do not inhibit the DNA excision repair process but apparently affect the effective DNA adduct load due to the ultimate species of DMBA metabolite responsible for hepatocellular DNA damage.
Environ Mol Mutagen 1987
PMID:Modulation of ultraviolet light-, ethyl methanesulfonate-, and 7,12-dimethylbenz[a]anthracene-induced unscheduled DNA synthesis by retinol and retinoic acid in the primary rat hepatocyte. 312 8

2-Bromo-(diglutathion-S-yl)hydroquinone [2-Br-(diGSyl)HQ] causes severe necrosis of the proximal renal tubules in the rat, elevations in blood urea nitrogen (BUN) and increased urinary excretion of protein, glucose, and lactate dehydrogenase. In contrast, 2-Br-3-(GSyl)HQ, 2-Br-5-(GSyl)HQ, and 2-Br-6-(GSyl)HQ caused differentially less toxicity than the diglutathionyl conjugate. None of these conjugates had any apparent effect on liver pathology and serum glutamate-pyruvate transaminase remained within the normal range. Pretreatment of rats with probenecid, an organic anion transport inhibitor, offered only slight protection against 2-Br-(diGSyl)HQ-mediated elevations in BUN, proteinuria, or glucosuria. In contrast, quinine, an organic cation transport inhibitor, potentiated the nephrotoxicity of 2-Br-(di-GSyl)HQ. Thus, in contrast to other nephrotoxic sulfur conjugates, probenecid-sensitive organic ion transport systems do not contribute to the kidney-specific toxicity of 2-Br-(diGSyl)HQ. However, inhibition of renal gamma-glutamyl transpeptidase by AT-125 completely protected rats from the nephrotoxic effects of 2-Br-(diGSyl)HQ. Aminooxyacetic acid, an inhibitor of cysteine conjugate beta-lyase, caused a 20-25% decrease in 2-Br-(diGSyl)HQ-mediated elevations in BUN and urinary excretion parameters. The isomeric 35S conjugates covalently bound to rat kidney 10,000 x g homogenate in the order 2-Br-6-(GSyl)HQ greater than 2-Br-5-(GSyl)HQ greater than 2-Br-3-(GSyl)HQ greater than 2-Br-(diGSyl)HQ. AT-125 (0.4 mM) decreased covalent binding by 25%, 17%, 33%, and 28%, respectively. Aminooxyacetic acid (0.1 mM) inhibited covalent binding by 26%, 10%, 17%, and 17% respectively. Ascorbic acid (1.0 mM) inhibited covalent binding by 63%, 87%, 62%, and 28%, respectively, and this inhibition correlated, inversely, with the redox potential of the conjugates. Thus, the covalent binding is mediated preferentially by oxidation of the quinol moiety, although the formation of reactive thiols cannot be excluded. In addition, the initial conjugation of 2-BrHQ with GSH does not result in the formation of a less redox-active species. However, the subsequent addition of a second molecule of GSH results in the formation of a more redox-stable compound, which, paradoxically, enhances toxicity. The metabolism of 2-Br-(diGSyl)HQ by renal proximal tubular gamma-glutamyl transpeptidase and trans-membrane transport of the cysteine conjugate(s) followed by oxidation of the quinol moiety is probably responsible for the target organ toxicity of this compound.
Mol Pharmacol 1988 Oct
PMID:2-Bromo-(diglutathion-S-yl)hydroquinone nephrotoxicity: physiological, biochemical, and electrochemical determinants. 317 33


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