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Biomedical subjects

D P Jones

Publications and source records attributed to D P Jones.

At least 19 recordsLinked to original sources
PubMed1992

Effect of chronic hypoxia on detoxication enzymes in rat liver.

Studies were performed to determine the effects of chronic hypoxia on enzymes that catalyze various detoxication reactions. Rats were exposed to room air or 10.5% O2 for 10 days, and microsomes and postmicrosomal supernatants were isolated from liver. Detoxication enzyme activities were measured by radiochemical and spectrophotometric assays, and immunoreactive protein amounts were measured by Western blot analysis. Total cytochrome P450, as measured by the CO-difference spectrum, and activities of superoxide dismutase (EC 1.15.1.1), epoxide hydrolase (EC 4.2.1.63), catalase (EC 1.11.1.6), glutathione disulfide reductase (EC 1.6.4.2), and glutathione (GSH) S-transferase (EC 2.5.1.18) were not affected by this extent of hypoxia. In contrast, 10 days of hypoxia decreased activities or immunoreactivities (% of aerobic) of GSH peroxidase (EC 1.11.1.9) (54%), cytochrome P450EtOH2 (42%), CYP3A1 (53%), sulfotransferase (EC 2.8.2.1) (77%) and UDP-glucuronosyltransferase (EC 2.4.1.17) (65%). Activity of glucose-6-phosphate dehydrogenase (EC 1.1.1.49), an important enzyme in NADPH production was also decreased to 56% of the aerobic value, but Western blot analysis showed that the amount of protein reactive with antibodies to glucose-6-phosphate dehydrogenase was not affected by hypoxia. Thus, hypoxia may decrease activity of enzymes by regulatory mechanisms even though the amount of immuno-detectable enzyme is unchanged. Liver cells isolated from rats exposed to hypoxia also gave lower GSH synthetic rates than cells from normoxic rats. This result, together with the effect of hypoxia on glucose-6-phosphate dehydrogenase, indicates that the GSH supply for GSH-dependent detoxication reactions may be limited due to chronic hypoxia. To test directly whether chronic hypoxia increased sensitivity to a compound normally detoxified by a GSH-dependent reaction, sensitivity to tert-butyl hydroperoxide (t-BuOOH) of hepatocytes from rats exposed to in vivo hypoxia was compared to that from normoxic rats. The results showed that the cells from the hypoxic rats were much more sensitive to injury. Taken together, these results suggest that decreases in amounts and/or activities of detoxication enzymes during chronic hypoxia may result in increased susceptibility of cells to chemical injury.

Animals↗
PubMed1992

Characteristics of taurine transport in cultured renal epithelial cell lines: asymmetric polarity of proximal and distal cell lines.

Taurine transport was determined in two continuous, renal epithelial cell lines: LLC-PK1 derived from the proximal tubule of the pig, and the Madin-Darby canine kidney cell (MDCK) from the distal tubule of the dog. In LLC-PK1, taurine transport is maximal at the apical surface, whereas in MDCK cells, transport is greatest at the basolateral surface. Transport is highly dependent on both sodium and chloride in the external medium, and is specific for beta-amino acids. The apical and basolateral surfaces of both cell lines show an adaptive response to extracellular taurine concentration, but only the basolateral surface of the MDCK cell responds to hyperosomolality by increased taurine accumulation. Thus, differential control of the beta-amino acid transport system by substrate and external tonicity exists. The role of the beta-amino acid transport system may differ according to the origin of the cell: in the proximal renal tubular cell, net transepithelial reabsorption of filtered taurine increases the body pool. By contrast, taurine accumulation by distal tubular cells may form a mechanism of cell volume regulation in response to osmotic stress.

Absorption↗
PubMed1992

Arteriovenous fistula after biopsy of renal transplant kidney: diagnosis and treatment.

An 11-year-old renal transplant recipient was noted to have a bruit over her transplant graft 26 months post transplant and 17 months following percutaneous renal biopsy during an episode of rejection. Diagnosis of an arteriovenous (AV) fistula was made by ultrasound examination with Doppler flow and was confirmed with arteriography. The AV fistula was occluded by transcatheter embolotherapy with placement of a steel coil into the fistula from the renal vein approach. This procedure allowed nonsurgical closure of the AV shunt without significant change in renal function.

Arteriovenous Fistula↗
PubMed1992

Pupillometer for clinical applications using dual 256-element linear CCD arrays.

A new pupillometer for measuring the size of the pupil of the human eye is described. It uses two inexpensive 256-element charge coupled device (CCD) arrays in an orthogonal configuration. The system is controlled and data are analysed by means of a Z80A microcomputer. Software allows the position and diameter of the pupil to be displayed on a monochrome video monitor. Infra-red diodes irradiate the eye so that measurements can be made in darkness. The accuracy is better than +/- 0.1 mm, over the range 3.2-9.5 mm. Dynamic measurements of the pupil light reflex response can be made with sampling periods as short as 20 ms.

Electronics, Medical↗
PubMed1992

Postanoxic oxidative injury in rat hepatocytes: lactate-dependent protection against tert-butylhydroperoxide.

Previous studies in this laboratory showed that hypoxia and anoxia enhance the susceptibility of hepatocytes to tert-butylhydroperoxide (TBH)-induced oxidative injury. To determine whether preceding exposure to anoxia affects postanoxic sensitivity to oxidative injury, viability was studied in hepatocytes incubated under anoxic conditions followed by reoxygenation without or with tert-butylhydroperoxide addition. Results showed that a preceding exposure to 60 min of anoxia substantially increased the vulnerability of cells to injury by the oxidant. Because substantial tissue lactate can accumulate during anoxia, the effect of increased lactate on postanoxic injury due to TBH was determined. Results showed that added lactate protected in a concentration-dependent manner. The TBH elimination rate was stimulated by lactate, and the pyruvate production rate approached the rate of TBH elimination. Thus, lactate protects against postanoxic oxidative injury by supplying reducing equivalents for peroxide reduction. This suggests that lactate accumulation during ischemia may be beneficial and that supplementation with lactate could be considered as a means to protect against postischemic injury.

Animals↗
PubMed1992

Glutathione in foods listed in the National Cancer Institute's Health Habits and History Food Frequency Questionnaire.

Glutathione (GSH) is an antioxidant and anticarcinogen that is present in plant and animal tissues that form the bulk of the human diet. Recent studies show that GSH is absorbed intact in rat small intestine and that oral GSH increases plasma GSH concentration in humans. To provide a database for epidemiological studies of dietary intake of GSH and risk of diseases in humans, we have measured the content of GSH in the foods listed in the National Cancer Institute's Health Habits and History Questionnaire. Foods were purchased in the Atlanta area and prepared as most commonly consumed in the United States. GSH analyses were performed using a high-performance liquid chromatography technique with a method of additions to correct for losses during sample preparation. A separate set of samples was run after treatment with dithiothreitol to measure the total of GSH and its disulfide forms (GSH). The results show that dairy products, cereals, and breads are generally low in GSH; fruits and vegetables have moderate to high amounts of GSH; and freshly prepared meats are relatively high in GSH. Frozen foods generally had GSH contents similar to fresh foods, whereas other forms of processing and preservation generally resulted in extensive loss of GSH. Thus this database will allow researchers to examine the relationship between dietary GSH and risk of cancers and other diseases.

Beverages↗
PubMed1992

Protective effect of the dimer of 16,16-diMePGB1 against KCN-induced mitochondrial failure in hepatocytes.

The dimer and trimer of 16,16-dimethyl-15-dehydroprostaglandin B1 (16,16-diMePGB1) previously have been shown to have protective effects on mitochondrial function. To examine the potential mechanisms involved in protection against mitochondrial failure, we have studied the effects of the dimer of 16,16-diMe-PGB1 (dicalciphor) on mitochondrial function in hepatocytes exposed to KCN. Addition of micromolar concentrations of dicalciphor provided substantial protection against KCN-induced toxicity in a concentration- and time-dependent manner. Dicalciphor, however, had no effect on total or mitochondrial ATP losses in KCN-treated cells. The dimer prevented the marked loss of mitochondrial membrane potential (delta psi) and delta pH that occurs as a result of KCN treatment and prevented KCN-induced loading of phosphate in mitochondria. Furthermore, the dimer of 16,16-diMePGB1 also prevented KCN-induced mitochondrial and cellular swelling. These results demonstrate that dicalciphor protects against KCN-induced damage and that this protection is associated with regulation of specific mitochondrial ion transport functions.

Adenosine Triphosphate↗
PubMed1992

Glutathione protection in alveolar type II cells from fetal and neonatal rabbits.

Previous studies have demonstrated a correlation between intracellular glutathione (GSH) pools and sensitivity to oxidative injury. In the present study, we demonstrated that de novo GSH synthesis or GSH uptake could increase intracellular GSH by 7- and 19-fold, respectively, in type II cells from neonatal rabbits. This suggested that the rate of GSH uptake was against a concentration gradient and greater than the synthetic rate. This increased intracellular GSH was associated with protection from oxidant injury by paraquat or 80% O2. A relationship between GSH uptake and protection was further supported by blockage of both processes by gamma-L-glutamyl-L-glutamate, a GSH analogue. With a greater oxidative burden, both de novo synthesis and GSH uptake were required to maintain protection. Although the transport rate was only 6% of that for neonatal cells, cells from fetal animals transported GSH and were protected from oxidative injury. From these results we conclude there was a causal relationship between GSH transport and protection from oxidative injury in type II cells from neonatal and fetal animals.

Amino Acids↗
PubMed1992

Protective effect of dicalciphor during mitochondrial failure.

Mammalian cells differ considerably in the duration of anoxia which they can tolerate despite the fact that dramatic bioenergetic changes occur rapidly. Previous studies indicate that the ability to tolerate anoxia is at least partly due to an endogenous signal transduction system that senses O2 deficiency and signal altered ion transport functions in the mitochondria. The responses included inhibition of ATP synthase, ADP/ATP exchange, inorganic phosphate uptake, mitochondrial swelling, and loss of the mitochondrial proton-motive force. An important distinction between KCN toxicity and anoxia is that KCN does not elicit these protective mechanisms. Thus, the ability of a compound to elicit these mechanisms in KCN-treated cells provides an assay for potential agonists of the endogenous protective mechanisms.

Animals↗
PubMed1992

Testifying in criminal court: emotional effects on child sexual assault victims.

Child victims must cope not only with the emotional consequences of criminal acts but also with the potentially traumatizing effects of legal involvement. Dramatic increases in the reporting of child sexual abuse are bringing greater numbers of children into contact with the criminal justice system, raising fears that child victims of sex crimes will be further harmed by the courts. In the present study, the effects of criminal court testimony on child sexual assault victims were examined in a sample of 218 children. From this sample, the behavioral disturbance of a group of "testifiers" was compared to that of a matched control group of "nontestifiers" at three points following testimony: 3 months, 7 months, and after prosecution ended. At 7 months, testifiers evinced greater behavioral disturbance than nontestifiers, especially if the testifiers took the stand multiple times, were deprived of maternal support, and lacked corroboration of their claims. Once prosecution ended, adverse effects of testifying diminished. In courthouse interviews before and after testifying, the main fear expressed by children concerned having to face the defendant. Children who appeared more frightened of the defendant while testifying were less able to answer the prosecutors' questions; and later, after the cases were closed, they were more likely to say that testifying had affected them adversely. The two most pervasive predictors of children's experiences in the courtroom, however, were age and severity of abuse. Despite relevant laws, few innovative techniques were used to help the children testify. The results are discussed in relation to children's ability to cope with stressful situations, the interaction of the legal system with the child/family system, and debates about the need to protect child victims who testify in criminal court.

Adaptation, Psychological↗
PubMed1992

Development of tubular function.

This article has reviewed the maturation of major renal tubular transport systems. The tubular reabsorption of certain amino acids and the secretion of organic acids, hydrogen ions, and potassium increases as a function of postnatal age, being relatively immature at birth, especially in the preterm infant. In contrast, the ability for phosphate reabsorption is enhanced during the immature state as the developing animal attempts to adapt to its environment. In the case of glucose, the transport system is relatively mature in the term infant and less so in the infant of less than 34 weeks' gestation. One should consider these developmental changes in the renal tubular transport of amino acids, potassium, phosphate, and organic acids in the nutritional assessment and pharmacologic treatment of preterm as well as term infants.

Acid-Base Equilibrium↗
PubMed1991

Effect of chronic hypoxia on acetaminophen metabolism in the rat.

The effect of chronic hypoxia (10.5% O2 for 8-9 days) on acetaminophen metabolism was studied in vivo or in isolated cell or microsomal systems. Results from in vivo studies with oral administration of acetaminophen showed that in hypoxic rats, the plasma appearance of the drug was delayed and the plasma half-life was increased. Analyses of the area under the curve (AUCoral) showed that this value was higher in hypoxic rats, whereas the rate constants for elimination (kelim) and absorption (kabs) were lower in these animals. Formation of the glucuronide and sulfate conjugates was decreased significantly (P less than 0.05) in hypoxic animals. The calculated volume of distribution (Vd) after an intravenous dose was not different in either group but total clearance (CL) was 35% lower in hypoxic rats. Studies with isolated hepatocytes from both groups revealed that glucuronidation and sulfation were inhibited markedly at low O2 concentrations. The O2 concentrations required for half-maximal production (P50 values) of glucuronide (2.3 microM O2) and sulfate (1.8 microM O2) conjugates in cells from hypoxic animals were lower than for control cells (5.3 microM and 3.9 microM O2 for glucuronide and sulfate conjugates, respectively). Maximal rates of conjugation in cells from hypoxic rats were 60-70% of control rates. Similar decreases in microsomal UDP-glucuronosyltransferase and cytosolic sulfotransferase activities were found in livers of animals exposed to chronic hypoxia. These lower P50 values are consistent with a lower P50 for oxidation of mitochondrial cytochromes in hypoxic cells. In comparison, the P50 for glutathione conjugation (4.1 microM O2) was not statistically different from control (4.6 microM O2), but the maximal rate was 65% higher. The results show that chronic hypoxia causes a change of absorptive processes and decreased glucuronidation and sulfation reactions which affects the disposition of acetaminophen and potentially the disposition of a variety of other exogenous and endogenous compounds.

Acetaminophen↗
PubMed1991

Calcium- and phosphate-dependent release and loading of glutathione by liver mitochondria.

The status of glutathione (GSH) was studied in isolated rat liver mitochondria under conditions which induce a permeability transition. This transition, which is inhibited by cyclosporin A (CyA), requires the presence of Ca2+ and an inducing agent such as near physiological levels (3 mM) of inorganic phosphate (Pi). The transition is characterized by an increased inner membrane permeability to some low molecular weight solutes and by large amplitude swelling under some experimental conditions. Addition of 70 microM Ca2+ and 3 mM Pi to mitochondria resulted in mitochondrial swelling and extensive release of GSH that was recovered in the extramitochondrial medium as GSH. Both swelling and the efflux of mitochondrial GSH were prevented by CyA. Incubation of mitochondria in the presence of Ca2+, Pi, and GSH followed by addition of CyA provided a mechanism to load mitochondria with exogenous GSH that was greater than the rate of uptake by untreated mitochondria. Thus, GSH efflux from mitochondria may occur under toxicological and pathological conditions in which mitochondria are exposed to elevated Ca2+ in the presence of near physiological concentrations of Pi through a nonspecific pore. Cyclical opening and closing of the pore could also provide a mechanism for uptake of GSH by mitochondria.

Animals↗
PubMed1991

Oral glutathione increases tissue glutathione in vivo.

Mice were given an oral dose of glutathione (GSH) (100 mg/kg) and concentrations of GSH were measured at 30, 45 and 60 min in blood plasma and after 1 h in liver, kidney, heart, lung, brain, small intestine and skin. In control mice, GSH concentrations in plasma increased from 30 microM to 75 microM within 30 min of oral GSH administration, consistent with a rapid flux of GSH from the intestinal lumen to plasma. Under these GSH-sufficient conditions, no increases over control values were obtained in GSH concentrations in most tissues except lung over the same time course. Mice pretreated for 5 days with the GSH synthesis inhibitor, L-buthionine-S,R-sulfoximine (BSO, 80 mumol/day) had substantially decreased tissue concentrations of GSH. Oral administration of GSH to these GSH-deficient animals gave statistically significant increases in GSH concentrations in kidney, heart, lung, brain, small intestine and skin but not in the liver. Administration of the equivalent amount of the constituent amino acids, glutamate, cysteine, and glycine, resulted in little change in GSH concentrations in all tissues in GSH-deficient animals. Thus, the results show that oral GSH can increase GSH concentrations in several tissues following GSH depletion, such as can occur in toxicological and pathological conditions in which GSH homeostasis is compromised.

Administration, Oral↗
PubMed1991

Stimulation of glutathione absorption in rat small intestine by alpha-adrenergic agonists.

The alpha-adrenergic agonist, phenylephrine (1.6 microM), caused a threefold stimulation of glutathione (GSH) transport from the lumen into the vasculature in isolated, vascularly perfused rat small intestine. Stimulation of GSH transport by phenylephrine was blocked by the alpha-adrenergic antagonists, prazosin or phentolamine. Norepinephrine and epinephrine (both alpha and beta agonists) also stimulated GSH absorption but not to the same extent as phenylephrine. Isoproterenol, a strict beta-adrenergic agonist, had no effect on the rate of GSH absorption. Under physiological luminal GSH concentrations, phenylephrine stimulated GSH efflux from the lumen, accumulation in the intestinal mucosa, and transport into the mesenteric vasculature. Phenylephrine did not stimulate the transport of polyethylene glycol, a high molecular weight molecule, and stimulated uptake of cysteine and glycine by 30%. This suggests that the effect of phenylephrine on GSH transport is not due to enhanced bulk flow through paracellular pathways. Studies with isolated small intestinal epithelial cells showed that phenylephrine also stimulated the release of GSH from the cells. Oral administration of phenylephrine with GSH caused a two- to fivefold transient increase in plasma GSH concentrations in rats. Phenylephrine alone or with the amino acid constituents of GSH caused no increase in plasma GSH concentration. Thus, absorption of dietary GSH is under hormonal regulation. The physiological importance of this regulation is not known, although such regulation may function to control utilization of dietary GSH for detoxication and may have therapeutic benefits for individuals with deficient GSH or increased risk of oxidative or chemically induced injury.

Adrenergic alpha-Agonists↗