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Biomedical subjects

R L Veech

Publications and source records attributed to R L Veech.

At least 55 records · Page 3Linked to original sources
PubMed1990

Cytochrome P450IIE1 is elevated in lymphocytes from poorly controlled insulin-dependent diabetics.

Cytochrome P450IIE1, a member of the cytochrome P450 supergene family, was measured in peripheral lymphocytes of 14 patients with insulin-dependent diabetes mellitus who were in poor metabolic control, as evidenced by elevated hemoglobin A1 levels (mean, 11.9 +/- 2.8%; normal, less than 7.8). Only one major form (mol wt, 48,000 daltons) of cytochrome P450IIE1 was detected with a specific polyclonal antibody against P450IIE1. Levels of cytochrome P450IIE1 were very low to undetectable in human lymphocytes from seven normal subjects. However, levels of P450IIE1 were elevated in lymphocytes from patients with insulin-dependent diabetes mellitus. Elevated levels of cytochrome P450IIE1 determined by immunoblot analysis correlate positively with the levels of hemoglobin A1 (r = 0.8), a metabolic indicator in diabetic subjects. In one study subject in whom diabetic control was improved, the drop in hemoglobin A1C levels was accompanied by normalization of P450IIE1 levels.

Adolescent↗
PubMed1990

Three genes for enzymes of the pyruvate dehydrogenase complex map to human chromosomes 3, 7, and X.

The genes for three proteins of the pyruvate dehydrogenase (PDH) complex have been assigned to human chromosomes by Southern analysis of a panel of human-rodent somatic cell hybrid DNAs with cDNA probes for these genes. PDH-E1 alpha has been localized on human chromosome 3p13-q23. The assignments of lipoamide dehydrogenase(E3) and PDH-E1 alpha [corrected] to chromosomes 7 and Xp, respectively, have been confirmed. Restrictive-fragment-length polymorphisms have been identified with E3, which will permit further localization of this gene by genetic linkage analysis.

Animals↗
PubMed1989

Induction of rat hepatic N-nitrosodimethylamine demethylase by acetone is due to protein stabilization.

The N-nitrosodimethylamine demethylase (P450I-IE1) is induced severalfold in liver by giving rats ethanol, acetone, pyrazole, and other related small molecular weight compounds. This induction is not the result of an increase in IIE1 mRNA, but could be due to either an increase in translation rate or a decrease in protein degradation. To determine the mechanism of induction, we measured IIE1 synthesis and degradation rates in untreated and acetone-treated rats. This was accomplished by immunopurification of radiolabeled IIE1 protein using a specific monoclonal antibody subsequent to in vivo labeling of total cellular protein with either NaH14CO3 or [3H]leucine. We found that in rats fed acetone, the rate of IIE1 synthesis was not changed; however, IIE1 degradation was markedly altered. In untreated rats, IIE1 protein was degraded via a biphasic pathway consisting of both a rapid and slow component with approximate half-lives of 7 and 37 h, respectively. However, in acetone-treated rats, only a monophasic curve with a half-life of 37 h was observed. The abolition of the rapid degradation component of the IIE1 turnover cycle indicates that induction of IIE1 by acetone is primarily due to specific stabilization of IIE1 protein. Since acetone is also metabolized by IIE1, we believe that this may be a substrate-induced enzyme stabilization.

Acetone↗
PubMed1988

The medical and metabolic consequences of administration of sodium acetate.

1. The standard total parenteral nutrition, peritoneal dialysis, hemodialysis and many surgical fluids in use today contain 36 to 45 mM D,L-lactate or 2 to 140 mM acetate whereas the normal blood level of D-lactate is 0.02 mM L-lactate 0.5 to 5 mM and acetate 0.1 nM. The reasons for the continued use in patients of such unphysiological concentrations of these anions appear to be historic. 2. Administration of similar concentrations of these anions to the rat causes widespread metabolic disturbances which mimic many of the untoward complications associated with current parenteral and dialysis therapy. Understanding of the mechanisms attendant upon the metabolism of these anions may serve as a guide for designing improved parenteral fluids for human patients. 3. Elevation of blood D-lactate to 5 mM is associated with cerebral dysfunction in human patients. 4. Acetate stimulates the release of the inflammatory leukokine, interleukin-1 from human monocytes. Use of 35 to 45 mM acetate in peritoneal dialysis fluids led to peritoneal fibrosis. Patients exposed to acetate containing hemodialysis fluids have 12-fold elevation in their plasma interleukin-1 levels. 5. Administration of 20 mM sodium acetate to rats leads to a number of metabolic disturbances similar to those seen in human dialysis patients: (a) Acetate elevates blood glucose in the rat and may contribute to the exacerbation of the carbohydrate intolerance seen in uremic patients. (b) Acetate increases the levels of hepatic malonyl CoA, the rate controlling substrate of fatty acid synthesis and may exacerbate the hypertriglyceridemia characteristic of dialysis patients. (c) Acetate administration in the rat leads to a decrease in the cytosolic phosphorylation potential, reduction of the redox state of the free cytosolic NAD couple and paradoxical oxidation of the mitochondrial NAD couple in a pattern analogous to that produced by uncouplers of oxidative phosphorylation and may account in part for the elevation of temperature reported in patients undergoing hemodialysis with acetate. (d) Acetate administration in the rat leads to an increase in intracellular phosphorylated intermediates, adenine nucleotides, inorganic phosphate, inorganic pyrophosphate, calcium and magnesium. On cessation of acetate metabolism, the inorganic phosphate and calcium accumulated intracellularly leave the intracellular space. In patients undergoing hemodialysis, the blood phosphate returns to predialysis levels, within 6 hr after the completion of treatment, leaving significant numbers of patients with chronic hyperphosphatemia and the multiple complications attendant to that state.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetates↗
PubMed1988

Ethanol inhibits some of the early effects of epidermal growth factor in vivo.

Charles River male Wistar rats (200-300 g) were meal fed for 9-10 days, injected with either saline, epidermal growth factor (EGF), ethanol, or ethanol combined with EGF and their livers were freeze clamped 5 min after intraperitoneal injection of EGF. Metabolites were measured and the redox state and phosphorylation potential were calculated. Epidermal growth factor alone elevated hepatic content of glucose 1-P, glucose 6-P, fructose 6-P, and 3-phosphoglycerate 1.2-1.3-fold when compared to saline treatment. Ethanol alone decreased hepatic content of 3-phosphoglycerate and phosphoenolpyruvate 3.2-3.7-fold below saline-treated levels. Ethanol, in combination with EGF, decreased hepatic values for 3-phosphoglycerate and phosphoenolpyruvate 2.0-2.3-fold from saline treatment but elevated the content of phosphoenolpyruvate 1.6-fold over ethanol treatment alone. Epidermal growth factor inhibited pyruvate kinase activity 1.3-fold when compared to saline controls but ethanol in the presence of EGF facilitated the recovery of activity of this enzyme.

Animals↗
PubMed1988

Role of the direct and indirect pathways for glycogen synthesis in rat liver in the postprandial state.

The pathway for hepatic glycogen synthesis in the postprandial state was studied in meal-fed rats chronically cannulated in the portal vein. Plasma glucose concentration in the portal vein was found to be 4.50 +/- 1.01 mM (mean +/- SE; n = 3) before a meal and 11.54 +/- 0.70 mM (mean +/- SE; n = 4) after a meal in rats meal-fed a diet consisting of 100% commercial rat chow for 7 d. The hepatic-portal difference of plasma glucose concentration showed that liver released glucose in the fasted state and either extracted or released glucose after feeding depending on plasma glucose concentration in the portal vein. The concentration of portal vein glucose at which liver changes from glucose releasing to glucose uptake was 8 mM, the Km of glucokinase [E.C. 2.7.1.12]. The rate of glycogen synthesis in liver during meal-feeding was found to be approximately 1 mumol glucosyl U/g wet wt/min in rats meal-fed a 50% glucose supplemented chow diet. The relative importance of the direct vs. indirect pathway for the replenishment of hepatic glycogen was determined by the incorporation of [3-3H,U-14C]glucose into liver glycogen. Labeled glucose was injected into the portal vein at the end of meal-feeding. The ratio of 3H/14C in the glucosyl units of glycogen was found to be 83-92% of the ratio in liver free glucose six minutes after the injection, indicating that the majority of exogenous glucose incorporated into glycogen did not go through glycolysis. The percent contribution of the direct versus indirect pathway was quantitated from the difference in the relative specific activity (RSA) of [3H] and [14C]-glycogen in rats infused with [3-3H,U-14C]glucose. No significant difference was found between the RSA of [3H]glycogen and [14C]glycogen, indicating further that the pathway for glycogen synthesis in liver from exogenous glucose is from the direct pathway. Our results do not support the thesis that the majority of liver glycogen is synthesized from glucose-6-phosphate derived from gluconeogenesis. Reasons for the discrepancy between current findings and other reports supporting the indirect pathway for glycogen synthesis in the liver are discussed.

Animals↗
PubMed1988

The measurement of D,L-2,3-butanediol in controls and patients with alcoholic cirrhosis.

Plasma D,L-2,3-butanediol was measured in 53 controls and 50 patients with alcoholic cirrhosis, none of whom had measurable amounts of blood ethanol. Thirteen of 50 samples from patients with alcoholic cirrhosis had measurable D,L-2,3-butanediol. (range less than 5-154 microM). In one patient with alcoholic cirrhosis who had been abstinent from ethanol for over 5 years plasma levels of D,L-2,3-butanediol ranged between 154 and 211 microM over a one-year period. Only one of the 53 control subjects had detectable levels of D,L-2,3-butanediol. Although it has previously been reported that 2,3-butanediol is present in alcoholics consuming distilled spirits (Rutstein et al. (1983) Lancet ii, 534), this is the first report of the persistent presence of these compounds in alcoholics in the absence of ethanol. Clearly in abstinent alcoholics the presence of 2,3-butanediol is not due to the ingestion of undistilled spirits nor is it likely to arise directly from the metabolic products of ethanol. The presence of D,L-2,3-butanediol in patients with alcoholic cirrhosis and its absence in control subjects suggests that this compound may be a marker of some forms for alcoholism.

Biomarkers↗
PubMed1988

Structure and regulation of the ethanol-inducible cytochrome P450j.

Specific polyclonal antisera against microsomal ethanol-inducible cytochrome P450 (P450j, P450IIE) were prepared and utilized to isolate cDNA for P450j from lambda gt11 cDNA libraries. The longest cDNAs encoding P450j of rat and human were completely sequenced. The rat P450j sequence was compared to those of other P450s (P450II gene family members) to determine the structural similarity. Southern-blot analysis of rat and human genomic DNAs verified that only a single gene shared extensive homology with P450j. Cloned P450j cDNA and antibodies were used to study the expression of P450j gene during development and by various inducers as well as in pathological conditions. By combination of cDNA hybridization and immunoblot analyses, three types of P450j gene expression were observed: transcriptional activation during development; post-transcriptional activation (probably via protein stabilization) by various inducers such as pyrazole, 4-methylpyrazole, acetone, and ethanol; and mRNA stabilization in diabetic and starved animals. These three different types of P450j induction appeared to be present not only in liver but also in lung and kidney tissues.

Animals↗
PubMed1988

Epidermal growth factor binding in the presence of ethanol.

Epidermal growth factor (EGF) is a mitogen which has been shown to stimulate maxillo-facial growth and DNA synthesis. Ethanol has been reported to inhibit cell regeneration in vivo and in vitro and to produce diminished maxillo-facial development in fetal alcohol syndrome. Recent findings from this laboratory have elucidated rapid metabolic changes in the hepatic content of some of the glycolytic intermediates resulting from injection of EGF, ethanol or EGF combined with ethanol in vivo. An immediate effect of EGF in vivo is to increase hepatic tissue content of 3-phosphoglycerate and phosphoenolpyruvate 1.2-1.3 fold when compared to saline treatment. Ethanol however causes a marked fall in the hepatic content of 3-phosphoglycerate and phosphoenolpyruvate 3.2-3.7 fold below saline treated levels. Ethanol in combination with EGF decreases hepatic values for 3-phosphoglycerate and phosphoenolpyruvate 2.0-2.3 fold from saline treated, but elevates the content of phosphoenolpyruvate 1.6 fold over ethanol treatment alone. Such metabolite changes occurring with ethanol treatment have been attributed alternately to redox shifts or to membrane perturbations. We wished to determine whether dimunition of 3-phosphoglycerate and or phosphoenolpyruvate below certain levels perhaps critically necessary for normal mitogenic action of EGF was due in this case to ethanol effects of binding of EGF to the cell membrane.

Cell Membrane↗
PubMed1987

Early metabolic effects of platelet-derived growth factor and transforming growth factor-beta in rat liver in vivo.

The short term metabolic effects of the in vivo administration of platelet-derived growth factor have been examined in the liver of the rat. Meal-fed male Wistar rats weighing between 150-180 g received an intraperitoneal injection of platelet-derived growth factor (17 units/100 g weight), transforming growth factor-beta (185 ng/100 g weight), or saline. At 5 min after injection, the livers were freeze-clamped. Samples of the tissue were subsequently assayed for metabolite content and enzyme activities. Platelet-derived growth factor injection caused an elevation in the liver content of pyruvate from 0.14 +/- 0.012 to 0.19 +/- 0.009 mumol/g wet weight liver (p less than or equal to 0.01) and an increase in the cytosolic phosphorylation potential [sigma ATP]/[sigma ADP][sigma Pi] from 6670 +/- 540 to 8970 +/- 750 (p less than or equal to 0.01). In addition an increase in the hepatic content of the hexose monophosphate pathway metabolites, 6-phosphogluconate (0.027 +/- 0.004 to 0.037 +/- 0.005 mumol/g wet weight) (p less than or equal to 0.05), ribulose 5-phosphate (0.013 +/- 0.001 to 0.017 +/- 0.001 mumol/g wet weight) (p less than or equal to 0.05) and combined sedoheptulose 7-phosphate and ribose 5-phosphate (0.052 +/- 0.007 to 0.062 +/- 0.004 mumol/g wet weight) (p less than or equal to 0.05) was observed. The elevation in the hexose monophosphate pathway metabolites resulted from a 1.3-fold elevation in the activity of glucose-6-phosphate dehydrogenase [EC 1.1.1.49] when measured in a crude homogenate. Kinetic analysis performed on partially purified glucose-6-phosphate dehydrogenase demonstrated no significant change in the Km of the enzyme for either NADP+ or glucose 6-phosphate, while a 2.4-fold increase in the Vmax was observed. In view of the rapidity of the change in total measured enzyme activity and increase in the Vmax of glucose-6-phosphate dehydrogenase, it is postulated that platelet-derived growth factor causes a covalent modification of the existing enzyme. Transforming growth factor-beta caused no change in the hepatic metabolite content in the treated animals when compared to saline treated controls.

Adenosine Diphosphate↗
PubMed1987

Relationship between intracellular pH and energy metabolism in dog brain as measured by 31P-NMR.

The relationships between pHi (intracellular pH) and phosphate compounds were evaluated by nuclear magnetic resonance (NMR) in normo-, hypo-, and hypercapnia, obtained by changing fractional inspired concentration of CO2 in dogs anesthetized with 0.75% isoflurane and 66% N2O. Phosphocreatine (PCr) fell by 2.02 mM and Pi (inorganic phosphate) rose by 1.92 mM due to pHi shift from 7.10 to 6.83 during hypercapnia. The stoichiometric coefficient was 1.05 (r2 = 0.78) on log PCr/Cr against pHi, showing minimum change of ADP/ATP and equilibrium of creatine kinase in the pH range of 6.7 to 7.25. [ADP] varied from 21.6 +/- 4.1 microM in control (pHi = 7.10) to 26.8 +/- 6.3 microM in hypercapnia (pHi = 6.83) and 24.0 +/- 6.8 microM in hypocapnia (pHi = 7.17). ATP/ADP X Pi decreased from 66.4 +/- 17.1 mM-1 during normocapnia to 25.8 +/- 6.3 mM-1 in hypercapnia. The ADP values are near the in vitro Km; thus ADP is the main controller. The velocity of oxidative metabolism (V) in relation to its maximum (Vmax) as calculated by a steady-state Michaelis-Menten formulation is approximately 50% in normocapnia. In acidosis (pH 6.7) and alkalosis (pH 7.25), V/Vmax is 10% higher than the normocapnic brain. This increase of V/Vmax is required to maintain cellular homeostasis of energy metabolism in the face of either inhibition at extremes of pH or higher ATPase activity.

Adenine Nucleotides↗
PubMed1987

Stabilization of cytochrome P450j messenger ribonucleic acid in the diabetic rat.

Cytochrome P450j, an enzyme involved in nitrosamine metabolism, is expressed in hepatic, pulmonary, and renal tissues and its level is elevated in ethanol- and acetone-treated rats as well as in diabetic rats induced by either streptozotocin or alloxan. Although P450j protein is substantially elevated by all inducing regimens, only in diabetic rats is P450j mRNA increased 10-fold. Nuclear run-on transcription analysis showed that this mRNA increase is not due to transcriptional activation but is due to specific stabilization of the P450j mRNA.

Animals↗
PubMed1987

The measurement of 1,2-propanediol, D, L-2,3-butanediol and meso-2,3-butanediol in controls and alcoholic cirrhotics.

Plasma 1,2-propanediol, D,L,-2,3-butanediol and 2,3-meso-butanediol were measured in 29 patients with biopsy proven alcoholic cirrhosis and 10 control subjects, none of whom had measurable blood alcohol levels. None of these compounds were present in control subjects at level above 5 nmol/ml. Seventeen (59%) of 29 serum samples drawn from patients with alcoholic cirrhosis contained 1,2-propanediol in concentrations above 5 nmol/ml (range less than 5.0 nmol/ml-35.4 nmol/ml, median 5.6), 8 (28%) of 29 samples contained D,L-2,3-butanediol in concentrations above 5.0 nmol/ml (range less than 5.0 nmol/ml-211 nmol/ml) and 7 (25%) of 29 samples contained meso-2,3-butanediol in concentrations above 5.0 nmol/ml (range less than 5.0-63.4 nmol/ml). In alcohol abstinent patients with alcoholic cirrhosis elevated serum 2,3-butanediol is due neither to ingestion of diols from undistilled alcoholic beverages nor is it likely to arise directly from the metabolic products of ethanol. In future studies on the origin of 2,3-butanediol in alcoholic patients biopsy evidence of the degree of associated liver damage should be obtained.

Alcoholism↗