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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CCl4 has been shown previously to be metabolized to the trichloromethyl radical (.CCl3) and to a novel oxygen-containing carbon dioxide anion radical (.CO2-) in the perfused rat liver and in vivo. Since the role of free radicals in CCl4-induced hepatotoxicity is unclear, these studies were designed to determine if a relationship between .CO2- formation and halocarbon-induced hepatotoxicity exists. CCl4 or bromotrichloromethane (CBrCl3) was infused into livers from control or phenobarbital-treated rats perfused with either nitrogen- or oxygen-saturated Krebs-Henseleit bicarbonate buffer. Samples of effluent perfusate and chloroform/methanol extracts of liver were analyzed by ESR spectroscopy for free radical adducts following infusion of halocarbon and the spin trap, phenyl-t-butylnitrone (PBN). Hyperfine coupling constants and 13C-isotope effects observed in the ESR spectra of organic extracts of liver demonstrated the presence of the PBN radical adduct of .CCl3 from both halocarbons. Radical adducts in aqueous extracts of liver and effluent perfusate had hyperfine coupling constants and 13C-isotope effects identical to those of PBN/.CO2- generated chemically from formate. The PBN/.CO2- radical adduct was also observed in urine following the intragastric administration of CBrCl3 and PBN. Detection of PBN/.CO2- adducts in the effluent perfusate was decreased 3- to 4-fold by DIDS (0.2 mM), an inhibitor of the plasma membrane anion transport system. The rate of formation of PBN/.CO2- was decreased 2- to 3-fold following inhibition of cytochrome P-450-dependent monooxygenases by metyrapone (0.5 mM) and was increased about 2-fold by induction of cytochrome P-450 by phenobarbital pretreatment. Toxicity of halocarbons in the perfused liver was assessed by measuring the release of lactate dehydrogenase (LDH) into the effluent perfusate in livers from phenobarbital-treated rats under conditions identical to those employed to detect radical adducts (i.e., during the infusion of CCl4 or CBrCl3 into livers perfused with either nitrogen- or oxygen-saturated perfusate). Under all conditions studied, PBN/.CO2- was detected in the effluent perfusate within 2-4 min. Metabolism of halocarbons to PBN/.CO2- was 6- to 8-fold faster during perfusion with nitrogen-saturated rather than with oxygen-saturated perfusate. Concomitantly, liver damage detected from LDH release occurred much sooner during halocarbon infusion in the presence of nitrogen-saturated rather than oxygen-saturated perfusate. A good correlation between the rate of formation of PBN/.CO2- and the time of onset of LDH release following halocarbon infusion was observed.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Pharmacol 1988 Mar
PMID:The carbon dioxide anion radical adduct in the perfused rat liver: relationship to halocarbon-induced toxicity. 283 23

The physiological and pathophysiological roles of protein kinase C activation were investigated in cultured mouse myocardial cells. First, effects of 12-O-tetra-decanoyl-phorbol-13-acetate (TPA), a potent activator of protein kinase C, on the intracellular pH (pHi) and cytosolic free Ca2+ level [( Ca2+]i) were studied, using 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF) and quin-2, respectively. In the presence of the Ca ionophore A23187, TPA induced a rise in pHi by activating amiloride-sensitive Na+/H+ exchange and also produced a rise in [Ca2+]i above that seen with A23187 alone. These effects were totally inhibited by amiloride. Second, the effect of TPA on hypoxia-induced myocardial cell injury was evaluated. The addition of TPA to the culture medium enhanced creatine kinase release from hypoxic myocardial cells (95% N2 + 5% CO2). This effect was markedly suppressed by the addition of amiloride. These data suggests that protein kinase C activation aggravates hypoxic myocardial injury, presumably by inducing Ca2+ overload. This event is secondary to activation of Na+/Ca2+ exchange through accelerated influx of Na+ into the cells as a result of Na+/H+ exchange stimulation by protein kinase C.
J Mol Cell Cardiol 1988 Jun
PMID:Protein kinase C activation aggravates hypoxic myocardial injury by stimulating Na+/H+ exchange. 285 Oct 54

Effects of glutamate on myocardial mechanical function and energy metabolism during 120 min of hypoxia and subsequent reoxygenation were studied in the isolated arterially perfused newborn and adult rabbit hearts. The muscle was perfused with a Krebs-Henseleit (KH) solution or KH solution which contained 1 mM glutamate. Glutamate attenuated the effects of hypoxia on mechanical function and tissue ATP concentration, and enhanced the recovery of mechanical function and tissue ATP during reoxygenation. During hypoxia, glutamate increased tissue succinate and GTP with no change in total lactate and pyruvate production. Trace studies using 14C-glutamate and the tissue homogenate showed that hypoxia increased tissue succinate and inhibited TCA cycle. Additional glutamate produced more CO2 and TCA intermediates in both oxygenated and hypoxic mediums. These data indicate that glutamate increased the rate of ATP production in the hypoxic and reoxygenated heart. This study shows that the improvement of mechanical function and ATP formation in the hypoxic myocardium by glutamate was due to an increase in both oxidative phosphorylation and substrate level phosphorylation. The effect of glutamate on the ATP and GTP production in the newborn heart was not different from the adult.
J Mol Cell Cardiol 1986 Sep
PMID:The effect of glutamate on hypoxic newborn rabbit heart. 287 83

Glycerol was demonstrated as an end product of anaerobic glucose metabolism in Trichomonas vaginalis and Tritrichomonas foetus, produced in addition to acetate, H2, CO2, and lactate or succinate. In T. vaginalis strain C-1, glycerol amounted to 16% of the fermentation products and was formed at an average rate of 38 nmol min-1 (mg protein)-1. Corresponding figures for T. foetus strain KV1 were 7% and 4.8 nmol min-1 (mg protein)-1. The amounts of glycerol detected compensated almost exactly for the deficits in fermentation products recognized earlier, thus complete redox balances can now be provided for both organisms. The metronidazole-resistant T. foetus strain KV1-1MR-100 excreted only negligible amounts of glycerol and carried out an ethanol-CO2 fermentation. Aerobiosis hardly affected glycerol formation in T. vaginalis strains C-1 and NYH 286, but almost completely abolished it in T. foetus strain KV1. An NADP-dependent glycerol 3-phosphate dehydrogenase and a Mg2+-dependent glycerol 3-phosphatase were detected in the cytosol of both species. The phosphatase is distinct from the particle-bound nonspecific acid phosphatase. Glycerol kinase activity was not detected in either organism. Enhanced pCO2 did not affect the ratio of fermentation products in T. vaginalis strain C-1, but significantly increased the amount of succinate, and decreased the amounts of acetate, H2, and CO2, formed by T. foetus.
Mol Biochem Parasitol 1986 Jul
PMID:Glycerol, a metabolic end product of Trichomonas vaginalis and Tritrichomonas foetus. 301 35

Ascaris suum L3 larvae isolated from rabbit lungs undergo the third ecdysis to L4 larvae after 3 days in culture under a gas phase of 85% N2/10% CO2/5% O2. The L3 larvae contain substantial malic enzyme activity and are capable of producing small amounts of the reduced organic acids characteristic of the fermentative pathways which operate in the adult. However, only a small portion of the total carbon utilized is accounted for by these reduced acids and their motility is cyanide-sensitive, suggesting that their energy-generating pathways are predominantly aerobic. In contrast, after ecdysis, the L4 larvae begin to utilize glucose at a greater rate and the proportion of total carbon utilized which is accounted for as propionate, 2-methylbutyrate and 2-methylvalerate also increases. In addition, motility becomes increasingly cyanide-insensitive, suggesting that these L4 larvae are able to utilize the anaerobic energy-generating pathways of the adult. Surprisingly, on day 10 in culture, these L4 larvae, although capable of producing reduced volatile acids, still retain substantial cyanide-sensitive cytochrome oxidase activity.
Mol Biochem Parasitol 1987 Jan 15
PMID:Biochemical changes during the aerobic-anaerobic transition in Ascaris suum larvae. 303 96

Hydrogenosomes isolated from Tritrichomonas foetus and Trichomonas vaginalis fermented pyruvate to acetate, malate, H2, and CO2 in an anaerobic process dependent on ADP, Pi, Mg2+, and succinate. The extent to which pyruvate was carboxylated to malate by malate dehydrogenase (decarboxylating) rather than decarboxylated to acetate by pyruvate/ferredoxin oxidoreductase was dependent on pCO2. The processes observed showed carbon and redox balances. The presence of an NADH/ferredoxin oxidoreductase activity was demonstrated. This enzyme is likely to be involved in the transfer of electrons from the ferredoxin reduced in pyruvate oxidation to NAD+ needed for the reductive carboxylation of pyruvate. Disruption of hydrogenosomes with Triton X-100 led to cessation of pyruvate-dependent H2 formation which could be restored by addition of coenzyme A and methyl viologen or ferredoxin. The formation of acetate and H2 by undisrupted hydrogenosomes proceeded at approximately half maximal rates in the presence of 25 microM succinate for T. foetus and 5 microM succinate for T. vaginalis. The apparent Km value of the acetate/succinate CoA transferase from T. foetus for succinate was approximately 45 microM, thus the stimulating effect of succinate might be due to the requirement of this enzyme for succinate. The exact mechanism of this effect remains to be elucidated, however.
Mol Biochem Parasitol 1986 Jul
PMID:Anaerobic pyruvate metabolism of Tritrichomonas foetus and Trichomonas vaginalis hydrogenosomes. 309 Apr 35

The ability of different substrates to affect myocardial function is well established but the mechanism for this effect has yet to be determined. To explore this area further, the studies described below were designed to determine the effect of different metabolic substrates, glucose or pyruvate, on myocardial response to hypercapnia. To assess this response, both the mechanical performance and the intracellular pH (pHi) were continuously measured. Intracellular pH was measured using the changes in absorbance of the vital staining dye, neutral red (NR). Although the presence of either substrate did not affect the response to hypercapnia, the addition of pyruvate was accompanied by a significant change in pHi. Specifically, there was a monotonic decrease in pHi comparable to that observed when PCO2 is increased from 5% to 10% (delta OD = -0.018 +/- 0.002 CO2; delta OD = -0.020 +/- 0.002 PYR, respectively). The mechanical response was similar for both; developed tension (tau) decreased initially (97 +/- 6% v. 93 +/- 8%) and then recovered (115 +/- 4% v. 101% +/- 5%). However, the changes in the maximum rate of relaxation, i.e. minimum time derivative: (tau mn) were dependent on the cause of the decrease in pHi. With hypercapnia, tau mn initially decreased and this was followed by a recovery phase which was 147 +/- 8% of the initial value. With pyruvate, tau mn decreased to 81 +/- 5% of control and was followed by no recovery. Because of the difference in the changes in tau mn, the effects of theophylline [3, 5] on these responses were determined. There was no effect on the response to an increase in PCO2. However, with theophylline present, the addition of pyruvate was accompanied by an increase in pHi (delta OD = + 0.005 +/- 0.001). The mechanical response was consistent with this increase and was similar to that seen when PCO2 is decreased from 10% to 5%. Specifically, there was an increase in tau (122 +/- 7%) followed by a small decrease (113 +/- 4%). Tissue assays for lactate showed a significant increase with the introduction of pyruvate. However, this increase was not affected by the presence of theophylline despite the opposite response of pHi. The data suggest that pyruvate affects myocardial function by altering pHi, and this effect is not due to an increase in lactate. In addition, the data are consistent with the model that the heart is capable of accommodating changes in pHi with only transient effects on contractile function.
J Mol Cell Cardiol 1986 Jul
PMID:A study of the effects of substrates on intracellular pH in toad ventricular strips. 309 40

Various hydrocarbons were synthesized by high-frequency discharge in a primordial terrestrial model atmosphere. The products were extracted by benzene or methanol and analyzed by GC-MS. The mean carbon chain length of the hydrocarbons formed by the discharge through pure CH4 gas was less than 6. Benzene was also obtained. Some isomers were obtained for each of the hydrocarbons containing a given number of carbons. When a small amount of C2H2 was added to the CH4, longer chain compounds were formed, as compared with discharge in CH4 only. However, when the amount of C2H2 was increased, unextractable high molecular weight compounds were produced. The amounts of products decreased as the mixing ratio of CO2 to CH4 increased. No hydrocarbons were detected when the ratio of CO2/CH4 exceeded 1.
J Mol Evol 1986
PMID:Synthesis of hydrocarbons under presumed prebiotic conditions using high-frequency discharge. 309 42

Isolated sheep cardiac Purkinje fibers were pulled through a latex membrane and both segments were independently superfused with modified Tyrode solutions. Transmembrane potentials and intracellular pH (pHi) were continuously measured in one segment (test compartment, TC), using double-barreled pH sensitive glass microelectrodes, while the internal H+ activity was altered in the adjacent part of the fiber (experimental compartment, EC). In the latter local pHi changes were produced by removal of CO2/HCO3-, by superfusing acidic (pH 6.8) solution, and by addition and subsequent withdrawal of NH4Cl. Withdrawal of CO2/HCO3- in EC was found to have no influence on pHi in TC at 0.35 to 1.0 mm distance. The action potential first shortened and later on prolonged above control duration after switching to HCO3- -free medium. Perfusing EC with an acidic solution had virtually no effect on pHi in TC while action potential duration (APD) increased. Addition and withdrawal of NH4+ in EC decreased, respectively increased, APD. In TC no change in pHi was observed at 0.8 to 1.0 mm distance. At shorter distance a slow acidification was seen, associated with the presence of NH4+ in EC. The presence of amiloride, a blocker of the pHi regulating mechanism, could not unmask a larger pHi change. It is concluded that, in cardiac muscle, large gradients of pHi are possible over a relatively short distance, while electrotonic interaction can produce changes in the time course of the action potential in neighbouring cells having a normal intracellular pH.
J Mol Cell Cardiol 1988 Mar
PMID:Influence of local intracellular pH changes on pH and action potentials in adjacent parts of cardiac Purkinje fibers. 313 14

To assess whether free radicals affect the characteristic sequence of events in an in vitro model of ischemia and reperfusion, isolated canine cardiac Purkinje fibers were exposed to anti-free radical agents, superoxide dismutase 50 U/ml; catalase 600 U/ml; mannitol 2 mM and 20 mM and combined superoxide dismutase, catalase, and mannitol 20 mM. Fibers were superfused for 60 min with altered Tyrode's solution which mimicked some conditions of ischemia (glucose-free, containing lactate, equilibrated with 90% N2-10% CO2), and then re-exposed to normal, oxygenated Tyrode's solution. Anti-free radical agents alone had no electrophysiological effects. Ischemic conditions resulted in moderate depolarization in most preparations (10 control; 43 treated) but in severe depolarization, to less than -60 mV, in some (3 control, 11 treated). Re-exposure to normal, oxygenated solution resulted in prompt initial hyperpolarization followed by marked depolarization, and finally by recovery to baseline maximum diastolic potential. Anti-free radical agents had not effect on maximum diastolic potential during exposure to ischemic conditions or on initial hyperpolarization following re-exposure to oxygenated solution. Preparations that became severely depolarized during exposure to ischemic conditions were not protected by anti-free radical interventions from developing marked depolarization following re-exposure to oxygenated solution. However, in fibers only moderately depolarized by the ischemic conditions, all anti-free radical interventions except mannitol, 2 mM significantly attenuated depolarization following re-exposure to oxygenated solution. Anti-free radical interventions significantly reduced the number of preparations that became markedly depolarized (to less than -65 mV) during re-exposure to oxygenated solution (except for mannitol, 2 mM). Agents had no effect on the occurrence of abnormal automaticity; the occurrence of inexcitability was reduced, but not significantly, except when all agents were used in combination. The results suggest that free radical production may contribute to electrophysiological abnormalities when Purkinje fibers are re-exposed to oxygenated Tyrode's solution after they have been exposed to ischemic conditions.
J Mol Cell Cardiol 1988 Nov
PMID:Electrophysiological effects of anti-free radical interventions in canine Purkinje fibers. 314 29


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