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Biomedical subjects

C M Schiller

Publications and source records attributed to C M Schiller.

15 recordsLinked to original sources
PubMed1986

Effects of adenine and its isomer 4-aminopyrazolo-[3,4-d]-pyrimidine on 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced mortality in rats.

Adult male Fischer rats were given a single po dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equal to 2 times the LD50 to increase the serum and liver lipid concentrations and to induce mortality. In addition, animals were given 4-aminopyrazolo-[3,4-d]-pyrimidine (4APP), an agent that decreases serum lipids, or adenine (Ad), an agent that prevents the formation of fatty liver, to examine the relationship between changes in lipids and TCDD-induced mortality. The principal effect of 4APP on TCDD-induced mortality (325 micrograms TCDD/kg body wt) was that it shortened the mean time to death. In contrast, Ad stimulated feed consumption and decreased body weight loss, but the mean times to death were similar for TCDD and TCDD + Ad animals. Based on these mortality studies, 4APP, but not Ad, affects the TCDD-induced mortality in Fischer rats. The TCDD-induced sensitivity to 4APP, based on decreased mean time to death, implies that blocking the release and/or synthesis of triglyceride-rich lipoproteins by the liver, and the subsequent decrease in serum lipids, may play an important role in the TCDD-induced mortality. The increase in serum triglyceride associated with TCDD exposure appears to be essential in providing metabolic energy under circumstances where lipoprotein retrieval is reduced.

Adenine↗
PubMed1979

Flow of reducing equivalents into isolated intestinal mitochondria.

A system of enzymes is required for the transport of reducing equivalents from reduced nicotinamide adenine dinucleotide (NADH) generated in the cytosol into the mitochondria by the substrate cycles. Also, the intestinal mitochondria must be capable of oxidizing the substrates of the cycles. Both substrate cycle enzymes and permeable mitochondria are necessary for the flow of pyruvate derived from glucose into the mitochondria for oxidative decarboxylation and for the efficient production of adenosine 5'-triphosphate (ATP) for the unique intestinal nutrient transport functions. Mitochondria from hamster intestinal mucosa were prepared exhibiting good respiratory control ratios. The isolated intestinal mitochondria would not oxidize NADH unless N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) was added as a carrier of reducing equivalents. The rates of oxidation of the substrates of the L-glycerol 3-phosphate and the L-malate/1-aspartate substrate cycles were measured with the mitochondria isolated from the small intestinal mucosa. The key enzymes measured in the cytosol and mitochondria from the mucosa were NAD-L-glycerol 3-phosphate dehydrogenase, Fp-L-glycerol 3-phosphate dehydrogenase, L-malate dehydrogenase and L-glutamate-oxaloacetate transaminase. In addition, the substrate cyclase were simulated in vitro by following NADH oxidation by isolated mitochondria in the presence of added cytosolic constituents.

Animals↗
PubMed1979

Chemical exposure and intestinal function.

The particular substances that are ingested by individuals are the consequence of their environmental, residential, and occupational exposures. The possible effects of these exposures on intestinal functions can be examined by the evaluation of in vivo or in vitro exposure followed by an in vivo and/or in vitro monitoring of effects. Several examples of the in vivo exposure and in vitro monitoring approach are presented to demonstrate the consequences of oral exposure to either a heavy metal (arsenic), or a herbicide contaminant (2,3,7,8-tetrachlorodibenzo-p-dioxin) or a jet fuel propellant (hydrazine) and the subsequent measurement of either a particular metabolic pathway, or a cell-specific enzyme induction or the development of brush border enzymes are presented.

Animals↗
PubMed1979

Studies of hepatic mitochondrial structure and function: morphometric and biochemical evaluation of in vivo perturbation by arsenate.

Ultrastructural morphometric and biochemical studies were conducted on hepatic mitochondria from control rats and rats treated in vivo with arsenate to examine changes in interrelationships between mitochondrial structure and biochemical functions. Morphometric analysis disclosed an over-all 1.2-fold increase in the relative mitochondrial volume density and 1.4-fold increase in the surface density of the inner mitochondrial membrane of arsenate-exposed rats. These structural changes were associated with a 1.5-fold increase in 14C-leucine incorporation into all mitochondrial proteins, which was primarily associated with the acid-insoluble membranous fraction. Mitochondria from arsenate-treated rats showed a marked disruption of normal conformational behavior with depression of nicotinamide adenine dinucleotide (NAD)-linked substrate oxidation and a resulting in vivo increase in the mitochondrial [NAD] to [NADH] ratio. Observed changes in mitochondrial membranes from arsenate exposure also resulted in 1.5- to 2-fold increases in the specific activities of the membrane marker enzymes monoamine oxidase, cytochrome oxidase, and Mg2+-ATPase. Activity of malate dehydrogenase, which is localized in the mitochondrial matrix, was unchanged. The results of this study demonstrate a positive quantitative in vivo correlation between mitochondrial structure and function and indicate a marked dependency upon membrane integrity for normal maintenance of the specific biologic activities performed by this organelle in vivo.

Animals↗
PubMed1978

The differential response of isolated intestinal crypt and tip cells to the inductive actions of 2,3,7,8-tetrachlorodibenzo-p-dioxin.

The cell specific induction of uridine diphosphate(UDP)-glucuronyltransferase by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in intestinal epithelium was studied by administering [14C] TCDD (8 microgram/kg to adult female rats). Intact epithelial cells from the tip and crypt regions were isolated by differential vibration of rat duodenum. Cell separation was monitored by electron microscopy and marker enzymes. UDP-glucuronyltransferase and radioactivity were assayed in both cell types 0 h, 3 h, 10 h, 1 day, 3 days and 5 days after treatment. UDP-glucuronyltransferase activities were not significantly changed in either cell type isolated from TCDD-treated rats until 24 hr after treatment when a three-fold increase in crypt cell activity was evident. No significant changes in UDP-glucuronyltransferase activity were observed in the differentiated tip cells until 3 days after TCDD treatment. UDP-glucuronyltransferase was increased approximately two-fold in both cell types from 3 and 5 days following TCDD treatment. There was a negative correlation between the time-course of UDP-glucuronyltransferase induction and the [14C]TCDD concentrations measured in these cells. These studies suggest that the undifferentiated cells of the intestinal crypt region are more sensitive to TCDD inductive actions than are the absorptive tip cells.

Animals↗
PubMed1978

Pyruvate metabolism after in vivo exposure to oral arsenic.

This study investigated altered pyruvate metabolism after prolonged oral arsenic exposure. Male rats were given access to deionized drinking water containing 0, 40 or 85 ppm sodium arsenate (As5+) for 3 weeks. Respiration studies with mitochondria isolated from treated animals indicated decreased state 3 respiration (with ADP) and decreased respiratory control ratios (RCR) for pyruvate/malate-mediated respiration, but not for succinate-mediated respiration, as compared to control respiration values. In addition, pyruvate dehydrogenase activity was measured, in both liver and intestine, before and after Mg-activation in vitro. After 3 weeks, the effects of arsenic at the highest dose level were pronounced on the basal pyruvate dehydrogenase activity (before activation) as well as the total pyruvate dehydrogenase (after activation). The inhibition of pyruvate dehydrogenase activity both before and after Mg-activation suggests an arsenic effect on mitochondrial pyruvate metabolism which, in part, involves inhibition of pyruvate decarboxylase. Evidence is also presented which may indicate an arsenic effect on the kinase and/or phosphatase which regulate pyruvate dehydrogenase activity.

Animals↗
PubMed1977

Pyruvate dehydrogenase activity in hamster small intestine during development.

Total pyruvate dehydrogenase activities in hamster intestine increase from 40 nmol/min (munits) per g of intestine in the foetal animals to 460 munits/g in the adult, whereas the fraction of the enzyme in the active form increases from 34 to 42% of the total activity over the same period. However, a complete conversion of the enzyme into the active form is observed in the neonatal animal immediately after birth. Results from experiments in vitro suggested that the activation of pyruvate dehydrogenase is controlled, in part, by the [NAD+]/[NADH] ratio. This proposal was tested in vivo by examining the proportion of the enzyme in the active form during conditions when the [NAD+]/[NADH] ratio was markedly altered, and the data show a direct relationship between the mitochondrial redox state and activity of the active form.

Animals↗
PubMed1977

Ultrastructural and biochemical effects of prolonged oral arsenic exposure on liver mitochondria of rats.

This investigation was undertaken to further delineate the subcellular manifestations of arsenic toxicity following chronic exposure using combined ultrastructural and biochemical techniques. Male rats were given access to deionized drinking water solutions containing 0, 20, 40, or 85 arsenic as arsenate (As(+5)) for 6 weeks. In situ swelling of liver mitochondria was the most prominent ultrastructural change observed. Mitochondrial respiration studies indicated decreased state 3 respiration and respiratory control ratios (RCR) for pyruvate/malate but not succinate mediated respiration. Specific activity of monoamine oxidase which is localized on the outer mitochondrial membrane showed increases of up to 150% of control and cytochrome-C oxidase which is localized on the inner mitochondrial membrane showed increases in specific activity of 150-200%. Activity of malate dehydrogenase which is localized in the mitochondrial matrix was unchanged at any dose level. These studies indicate that decreased mitochondrial respiration is only one aspect of arsenic toxicity to this organelle. Marked arsenic-mediated perturbation of important enzyme systems localized in mitochondria which participate in the control of respiration and other normal mitochondrial functions are also important manifestations of cellular dysfunction.

Administration, Oral↗
PubMed1977

Effects of arsenic on pyruvate dehydrogenase activation.

Our studies illuminate a particular site of altered pyruvate utilization by liver mitochondria isolated from arsenic-fed rats. Initially, pyruvate dehydrogenase (PDH) levels were measured before and after in vitro activation. The liver homogenates were prepared from male rats given access to deionized drinking water solutions containing 0, 20, 40, and 85 ppm arsenic as sodium arsenate (As+5) for 3 and 6 weeks. After 3 weeks, the effects of arsenic at the highest dose level were pronounced on the basal activity (before activation), with inhibition up to 48% of the control values. The total PDH (after activation) was inhibited by 14, 15, and 28% of the control values at 20, 40, and 85 ppm As+5, respectively. A similar pattern of inhibition of PDH was observed at 6 weeks, although the inhibition was lower at the highest dose. This effect is probably a reflection of mitochondrial regeneration at this time and dose. The inhibition of PDH both before and after activation suggests a direct arsenic effect on pyruvate utilization which does not involve a lipoic acid moiety. Evidence is also presented which indicates an arsenic effect on the regulating kinase and/or phosphatase. The metabolic effects of impaired mitochondrial utilization by pyruvate are also discussed.

Animals↗
PubMed1977

Isolation and characterization of four peptide hydrolases from the cytosol of rat intestinal mucosa.

The high speed supernatant fluid prepared from rat intestinal mucosa was subjected to ion-exchange chromatography on diethlaminoethyl-cellulose eluted with a linear gradient of sodium chloride (0 to 0.27 M). Assay of eluted fractions for Phe-Gly hydrolase activity revealed four distinct peaks of enzyme activity. These cytosol enzymes have been designated I, II, III, and IV in order of their elution from the column. Examination of the substrate specificity of the four enzymes by use of 20 mM peptide concentrations indicated the most discriminating substrates for the four enzymes were Leu-Gly-Gly, His-Met, Ser-Phe, and leucine amide, respectively. The mean distribution of the recovered peptide hydrolase activities against these substrates among the four enzymes I, II, III, and IV was 96.1, 1.4, 1.7, and 0.8%, respectively, for Leu-Gly-Gly; 0.6, 96.4, 2.4, and 0.6% for His-Met; 0, 0, 95.8, and 4.2% for Ser-Phe; and 20.8, 19.8, 5.6, and 53.8% for leucine amide. Ion-exchange chromatography resulted in increases in specific activity of 19-, 19-, 46-, and 3.5-fold for enzymes I, II, III, and IV, respectively. The activity of all four enzymes, but especially III and IV, were stabilized by the presence of 150 muM dithioerythritol. Activity of each of the four enzymes was decreased 79 to 100% by 1mM ethylenediaminetetraacetate, HgCl2, 1, 10-phenanthroline, or 0.5 mM p-hydroxymercuribenzoate, except that the activity of enzyme I was decreased only 15% by ethylenediaminetetraacetate. No significant activation of the partially purified enzymes occurred in the presence of 500 muM Zn++, Co++, or Mg++. The four enzymes exhibited distinct pH profiles with optima at 7.5, 7.5, 8.5, and 8.0 for enzymes I, II, III, and IV, respectively. Molecular weights of the four enzymes determined by gel filtration on Sephadex G-200 were 58,500, 74,000, 97,500, and 113,000, respectively. All four enzymes lost more than 85% of their activity after 1 hr at temperatures of 50 degrees C or higher in sodium phosphate buffer, pH 7.0. The Km values determined with the most specific substrates for each enzyme were 0.76, 0.44, 3.82, and 8.3 mM for enzymes I, II, III, and IV, respectively. Recent evidence suggests that a significant amount of some small peptides are absorbed intact and hydrolyzed by cytosol peptide hydrolases. Adequate understanding of the function and control of these intracellular enzymes requires knowledge of the characteristics and substrates specificity of individual enzymes. The study described here demonstrates the presence of at least four cytosol peptide hydrolases with distinct substrate specificities. Substrates almost exclusively hydrolyzed by each of three of the enzymes, and therefore suitable for assay of each of these enzymes in the presence of the others, have been identified.

Animals↗
PubMedDate not supplied

Processes of transport and absorption in the developing infant intestine.

An understanding of changes in the processes of absorption, detoxification, and intoxication in the intestine of infants, especially during the perinatal period, may aid in reaching an understanding of why the syndrome of infant botulism is restricted to the first six months of life. Some of the important metabolic changes associated with both the perinatal and the postnatal period of development are emphasized in these studies. A more complete understanding of the processes by which substances are absorbed into the intestine and then reexposed via the enterohepatic circulation may provide clues about why infant botulism occurs.

Adenosine Triphosphate↗