Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Unexpectedly large differences in the tissue patterns of lactate dehydrogenase-C (Ldh-C) gene regulation were observed among species of fish within the family Umbridae (Salmoniformes). Normally, all the species within a family or order of advanced fishes exhibit the same, tissue-restricted pattern of L-lactate dehydrogenase C4 isozyme synthesis--either eye- or liver-restricted expression, but not both. However, within the Umbridae the more anciently derived species had a more generalized (primitive) tissue expression, whereas the more recently derived species had a more tissue-restricted expression, predominating in the eye. Given the relative divergence times among the species estimated by genetic distance (using 51 protein-coding loci), divergence from the presumed primitive expression of the Ldh-C gene appears to have been proceeding more rapidly in some species lineages than others. This narrowing of Ldh-C gene tissue regulatory specificity within the family Umbridae is similar to the general trend observed over much greater evolutionary times within the class of bony fishes. The results support the hypothesis of repeated evolutionary canalizations of Ldh-C gene regulation from the generalized tissue expression in more primitive species to a predictable tissue-restricted expression (in either eye or liver) in advanced species. Furthermore, in the Umbridae, this progressive restriction of tissue expression of isozymes has taken place during the evolution of both the Ldh-C and Ldh-B genes. These evolutionary trends in the regulation of isozyme-locus tissue expression in the bony fishes are consistent with either an intrinsically conditioned trend of change in gene regulation or with a response to natural selection.
J Mol Evol 1986
PMID:An apparent progressive and recurrent evolutionary restriction in tissue expression of a gene, the lactate dehydrogenase-C gene, within a family of bony fish (Salmoniformes: Umbridae) 309 46

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

The influence of solvent viscosity on the kinetic parameters of the pyruvate reduction reaction catalyzed by lactate dehydrogenase has been investigated. The viscosity was adjusted by sucrose and glycerol solutions at concentrations from 0 to 44% and from 0 to 63%, respectively. The reaction rate decreased abruptly with an increase in viscosity. The study of different reaction stages (enzyme-substrate complex formation, catalysis, inhibitory complex decomposition, competitive inhibition by chlorine ions) revealed that the catalysis (and the related conformational changes) is the only stage (of the above mentioned) that depends markedly on the solvent viscosity. The reaction is insensitive to the changes in the dielectric properties of the solution induced by the addition of alcohols and dioxane. The observed power dependence of the rate constant on viscosity is explained in terms of Kramer's theory which considers the proton transition through the activation barrier to be a diffusion in the field of random forces. The influence of solvent viscosity on enzymic kinetics indicates a direct relation between solvent dynamics and relevant protein conformational movements.
Mol Biol (Mosk)
PMID:[Dynamic aspect of kinetics of reaction catalyzed by lactate dehydrogenase]. 318 25

Doxorubicin is an important anticancer drug that undergoes redox cycling leading to the production of oxygen radicals; however, its clinical use is limited by toxicity. Redox cycling due to doxorubicin was assessed in the perfused rat liver from increases in O2 uptake by the organ, and toxicity was determined from lactate dehydrogenase release and trypan blue uptake. Doxorubicin increased O2 uptake in a concentration-related manner with half-maximal increases at about 100 microM drug. Within 5 min after addition of 300 microM doxorubicin, lactate dehydrogenase was detected in the effluent perfusate. Enzyme release increased steadily and reached values of 600 units/liter after 60 min. Rates of O2 uptake due to redox cycling of doxorubicin (300 microM) increased by 57 mumol/g/hr in oxygen-rich (mean [O2] = 473 microM) periportal regions of the liver lobule, but did not change in pericentral regions where O2 tension was lower [( O2] = 247 microM). Concomitantly, fluorescence of NAD(P)H measured from the liver surface decreased in periportal but not pericentral regions. The zone-specific decrease in NADPH was attributed to redox cycling of doxorubicin. Trypan blue was taken up exclusively by cells in periportal regions of the liver lobule after perfusion with doxorubicin. When the average O2 tension was lowered from 550 to 200 microM, O2 uptake due to redox cycling of doxorubicin in periportal regions was reduced 3-fold and toxicity was abolished, indicating that toxicity due to doxorubicin is oxygen-dependent. Redox cycling of doxorubicin was minimal in regions of the perfused liver where the O2 concentration was below 400 microM. In contrast, isolated microsomes displayed maximal changes in O2 uptake due to redox cycling of doxorubicin at O2 tensions of about 10 microM. Thus, oxygen per se is not rate-limiting for redox cycling of doxorubicin in the intact organ. Since NADPH is also required for redox cycling of doxorubicin, the effect of oxygen on the ability of mitochondria and the pentose cycle to supply reducing equivalents for redox cycling of doxorubicin was examined. NADPH supply from the pentose cycle was reduced by fasting while that from mitochondria was inhibited by cyanide. The increase in O2 uptake due to redox cycling of doxorubicin was around 60 mumol/g/hr in livers from fed or fasted rats. In the presence of potassium cyanide, stimulation of O2 uptake by doxorubicin was reduced by about one-half in livers from fed rats (29 mumol/g/hr) yet was abolished nearly completely in livers from fasted rats (7 mumol/g/hr).(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Pharmacol 1988 Nov
PMID:Oxygen-dependent hepatotoxicity due to doxorubicin: role of reducing equivalent supply in perfused rat liver. 319 59

The respective roles of exogenous polyunsaturated fatty acids on the lipid composition, physiological properties and enzyme release was investigated on isolated cardiac muscle cells in normoxia and hypoxia. Rat neonatal ventricular myocytes were grown for 5 days in conventional serum-supplemented medium. Cells were then incubated for 24 h in fully chemically-defined media featuring a balanced fatty acid composition containing either linoleic acid (18:2 n-6) or linolenic acid (18:3 n-3) as sole polyunsaturated fatty acid source. Transmembrane potentials were monitored with microelectrodes and contractions with a photoelectric device. The radio of n-6 to n-3 phospholipid fatty acids increased from 6.3 in control cells to 20.2 in cells exposed to n-6 fatty acids (SM6) and decreased to 1.4 in those exposed to n-3 fatty acids (SM3). These modifications had no influence on the electrical and mechanical activities and on automaticity in normoxic conditions. The action potential depression under hypoxia was less severe in SM6 cells, whereas there was a better electrophysiological recovery upon reoxygenation in SM3 cells. However, the loss of lactate dehydrogenase during sustained hypoxic treatment was not affected by changes in phospholipid fatty acid pattern. These results suggest that the effect of the polyunsaturated fatty acid balance depends on the cellular function under study and on the environmental conditions.
J Mol Cell Cardiol 1988 Oct
PMID:Modification of the n-6/n-3 fatty acid ratio in the phospholipids of rat ventricular myocytes in culture by the use of synthetic media: functional and biochemical consequences in normoxic and hypoxic conditions. 321 98

Kinetic models for enzyme reactions are considered which take into account enzyme and substrate isomerization. Application of graph-theoretic methods allows to reveal fragments in schemes which may induce multiple stead-states or concentrational selfoscillations. The role of substrate isomers in the inhibition of enzyme isomers to produce critical phenomena is considered. The boundaries of parameter domains for critical phenomena are estimated. It is shown that the controlled change in concentrations of substrate and enzyme isomers may be important in regulation of enzyme systems, if different enzyme isomers are inhibited mainly by different substrate isomers. The models are used for interpretation of possible critical phenomena in the open reaction catalyzed by lactate dehydrogenase. It is shown that lactate dehydrogenase may act as a trigger in carbohydrate metabolism by changing "critically" its activity in relation to changes in pH and pyruvate fluxes. Slow enzyme inhibition by enolpyruvate is suggested as a possible reason for glycolytic oscillations.
Mol Biol (Mosk)
PMID:[Simple kinetic models explaining critical phenomena in enzymatic reactions with isomerization of the enzyme and substrate]. 322 58

Coenzyme Q10 (CoQ10) was studied in papillary muscle from 18 patients (52-67 years, 2 females) subjected to open heart surgery due to mitral valve disease. In addition the enzyme activities of lactate dehydrogenase (LD) with its five isozymes, citrate synthase (CS) and mitochondrial CK (CK-MIT) were determined. Myocardial function was assessed by means of left ventricle (LV) angiography. CoQ10 averaged 0.39 (range 0.26-0.59) micrograms x mg-1 dw. On an individual basis CoQ10 was related to CS activity although not as closely as CK-MIT (r = 0.45, p less than 0.05 versus r = 0.86, p less than 0.001). The ratio (CoQ10) x (CS activity)-1 was calculated to represent mitochondrial quality. The level of LD3 fraction increase was used to mark for the degree of metabolic stress in the heart. LD3 fraction was negatively related to the quality index (r = -0.71, p less than 0.001). Thus, those with a low CoQ10 per unit of CS activity had also a high LD3 isozyme fraction. In a subset of 12 patients with isolated mitral regurgitation due to myxomatous valve degeneration, CoQ10 and the ratio CoQ10 over CS decreased with the degree of LV function impairment (r = -0.58, p less than 0.05 and r = -0.68, p less than 0.05, respectively). The quality index takes into account not only enzyme activity but also the potential for control of free oxygen radicals.
Mol Cell Biochem 1988 Nov
PMID:Coenzyme Q10 and key enzyme activities in papillary muscle related to left ventricle function in mitral valve disease. 323 Dec 16

Readmission of Ca2+ after a short period of Ca2+-free perfusion results in a rapid and massive release of cytoplasmic proteins from the heart (calcium paradox). Maximal release rates of proteins are already reached within 2 min after Ca2+ repletion. The precise mechanism underlying the loss of cellular membrane integrity, resulting in the loss of intracellular proteins, has not been clearly defined. The present study indicates that neither substantial degradation of phospholipids, being important constituents of myocardial membranes, nor accumulation of fatty acids occur during the early phase (within 1.5 min) of Ca2+ readmission. Thereafter significant amounts of such fatty acids as arachidonic acid accumulate in the Ca2+ repleted hearts. The late onset of arachidonic acid accumulation, most likely reflecting phospholipid degradation, is considered to be an epiphenomenon occurring in myocardial cells which became heavily damaged, as indicated by the substantial loss of lactate dehydrogenase, during the early phase of Ca2+ repletion. Interestingly, tissue fatty acid levels increased already significantly during the Ca2+-free perfusion period (by about 240%). The significance of this finding is not completely understood. A possible causal relationship with disturbed ion homeostasis during the induction of calcium paradox remains to be established.
J Mol Cell Cardiol 1988 Jul
PMID:The myocardial content of fatty acids and phospholipids during the calcium paradox. 326 70


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