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Biomedical subjects

S N Pennington

Publications and source records attributed to S N Pennington.

At least 37 records · Page 2Linked to original sources
PubMed1985

Biochemical interactions of ethanol with the arachidonic acid cascade.

A rapidly increasing scientific literature now supports the possibility of an alcohol-prostaglandin interaction. This chapter reviews evidence for both direct and indirect biochemical interactions between ethanol and the metabolism of arachidonic acid and several related compounds. Much of the present data is based on pharmacological manipulation of prostaglandin (PG) levels by potent nonsteroid anti-inflammatory agents such as indomethacin. Indomethacin markedly alters the behavioral response to ethanol, particularly in the mouse model. These data suggest that PGs are involved in the behavioral response to acute ethanol exposure in the mouse. In other animal models, alcohol has been reported to alter blood platelet metabolism of arachidonic acid, to suppress the enzymatic degradation of PGs, and to alter the response of the adenyl cyclase system to several hormones including PGs of the "E" series. In humans, both the stimulation and inhibition of PG synthesis is reported to aid the treatment of various aspects of alcoholism. Further, PGs are reported to protect against alcohol-induced fatty liver, and both PGs and arachidonic acid protect the gastric mucosa against ethanol-induced lesions. Certainly the residual consequences of acute, excessive ethanol consumption are commonly treated with a prostaglandin synthesis inhibitor. The material in this chapter is an attempt to review the data and to discuss the molecular mechanism underlying these observations.

Animals↗
PubMed1984

Alcohol dehydrogenase activity in the developing chick embryo.

Before day 9 of incubation, chick embryos contain no measurable alcohol dehydrogenase (ADH) activity. Following day 9 of incubation, chick embryo liver ADH activity increases as a linear function of liver mass. A single dose of ethanol given at the start of incubation is cleared only slowly prior to day 9 of incubation but is completely cleared by day 13. Chick embryo liver ADH has two detectable isozymes throughout development. The percentage contribution of each isozyme to total ADH activity does not change significantly during development. The Km apparent of chick liver ADH is significantly increased shortly after hatching relative to the Km apparent of embryonic ADH. Ethanol exposure during incubation has no effect on the development of ADH activity or isozyme distribution.

Alcohol Oxidoreductases↗
PubMed1983

Kinetic changes in rat renal 15-hydroxy-prostaglandin dehydrogenase induced by chronic ethanol exposure.

Several lines of investigation have suggested that exposure to ethanol may lead to alterations in both the synthesis and degradation of the E and F series of prostaglandins (PG). It has been suggested that these changes in PG metabolism underlie certain of the pathophysiological consequences of chronic alcoholism but few data are available as to the mechanism responsible for these changes. We now report that chronic exposure to ethanol in moderate doses (17% total dietary calories as ethanol) and high doses (35% total dietary calories as ethanol) results in a concentration dependent loss of renal 15-hydroxy-prostaglandin dehydrogenase for the NAD mediated reactions. Soluble fractions of kidney homogenates in the presence of greater than 10 Km concentrations of NAD exhibited dose dependent loss of specific and total organ PG dehydrogenase activity toward PGE2 and F2 alpha. A similar dose dependent decrease in the Vmax of the NAD mediated reaction was measured for the oxidation of PGE1, E2, and F2 alpha. Moderate doses of ethanol resulted in an increase in the Km for PGE2 and F2 alpha. Km values for the NADP mediated reactions were not significantly influenced by exposure to high doses of ethanol other than for PGE1. These data suggest that chronic ethanol consumption results in a dose dependent, selective inhibition of the metabolism of PGs of the "2" series by the renal PGDH enzyme which utilizes NAD.

Animals↗
PubMed1980

The effect of ethanol on the metabolism of prostaglandins and related compounds.

Previous studies have shown that chronic consumption of ethanol by rats lowers the level of membrane-bound arachidonic acid (C20:4) and stimulates the in vitro measured rate of hepatic lipid peroxidation. These observations suggested that ethanol might thereby cause changes in the metabolic pathway leading to prostaglandins and related compounds. Initial studies demonstrated that chronic ethanol administration to male rats results in an impaired ability on the part of these animals to catabolize prostaglandins via renal prostaglandin dehydrogenase (PGDH) but no effect was observed on the synthesis of thromboxanes by blood platelets from these same animals. Experiments have now been carried out in an attempt to further assess the acute and chronic effects of ethanol on the metabolism of prostaglandins and prostacyclin. Generally, these results suggest a lack of an acute effect of ethanol and a dose dependency for the chronic effects.

Aging↗
PubMed1980

Alterations in maternal and fetal prostaglandin dehydrogenase as a result of maternal ethanol consumption.

Various lines of research have suggested that ethanol consumption may alter prostaglandin-related physiology. Our laboratory has reported that chronic exposure to high doses of ethanol lowers the ability of kidney and lung homogenates from rats to catabolize prostaglandin E2 and F2 alpha via 15-prostagladin dehydrogenase (PGDH). Because of the apparently unique role played by prostaglandins in conception, growth and development of the fetus and parturition, we have attempted to determine if the alterations observed in male rats also occur in females and if any alterations in fetal metabolism result from maternal ethanol exposure. Further, we have measured the influence of ethanol administration on renal clearance of the 15-keto metabolite of PGF2 alpha in an attempt to determine the in vivo significance of the enzyme inhibition observed in vitro. Initial results indicate the following. 1) Female Holtzman rats doses at 2.0, 5.0 and 7.0 mg ethanol/kg during the first, second, and third trimesters of pregnancy, respectively, showed losses in renal PGDH activity similar to those found in males (1.52 versus 1.05 picomole/min/mg, p < 0.001 by matched t-test). 2) Placental tissue (amnion) isolated from these same animals on day 21 of the pregnancies also showed a significant decrease in PGDH activity (14.79 versus 11.77 picomoles/min/mg, p < 0.01). 3) Kidney homogenates from fetuses delivered on day 21 of the pregnancies showed a significant increase in PGDH relative to pair-dosed controls (16.77 versus 12.65 picomoles/min/mg, p < 0.01). 4) In a separate experiment, urinary clearance of PGF2 alpha metabolite was inhibited in a dose related manner up to a level of 6 gm/kg.

15-Oxoprostaglandin 13-Reductase↗
PubMed1979

The effect of dietary vitamin E on indomethacin stimulated chemiluminescense in rat liver microsomes.

Peroxidation of endogenous lipid by rat liver microsomes, coupled with oxidation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) was markedly stimulated in the presence of indomethacin [1-(p-chlorobenzyl)-5-methoxy-2-methyl-3-indole acetic acid], a potent anti-inflammatory drug. This system also generated a rapidly developed chemiluminescense (CL), the intensity and rate of development of which were related to indomethacin concentration and the amount of peroxidation in the sample. Microsomes from rats fed a liquid diet based on Sego diet drink (Pet Incorporated) failed to chemiluminesce with or without added indomethacin. Supplementation of the Sego diet with a polyunsaturated fatty acid (C18:3) did not restore the chemiluminescense. In vitro and in vivo studies indicate that vitamin E (a component of the Sego liquid diet) inhibited the microsomal chemiluminescense reaction in a dose related manner.

Animals↗
PubMed1979

The effect of ethanol on thromboxane synthesis by blood platelets.

The synthesis of thromboxane A2 (measured as TXB2) by blood platelets in the presence of ethanol and in platelets from animals dosed chronically with ethanol has been examined. Neither acute nor chronic exposure of guinea pig platelets to ethanol altered thromboxane synthesis. Measurement of total products indicated that neither fatty acid cyclooxygenase nor platelet lipoxygenase was influenced by blood ethanol levels generally associated with intoxication. In human platelets, very high levels of ethanol inhibited thromboxane synthesis in a dose related manner. These results are contrary to reports that high doses of ethanol stimulate arachidonate cyclooxygenation.

Animals↗
PubMed1978

Effect of sucrose on lipogenesis of rats chronically treated with ethanol.

The effect of chronic ethanol administration with and without sucrose on the lipogenic enzymes of liver and adipose tissue of rats was studied. Ethanol markedly influenced the adipose lipogenic enzymes at 28 days. Sucrose caused a 2-10fold increase in lipogenic enzymes of both adipose and liver.

ATP Citrate (pro-S)-Lyase↗
PubMed1978

Indomethacin stimulation of lipid peroxidation and chemiluminescense in rat liver microsomes.

Peroxidation of endogenous lipid by liver microsomes, coupled with oxidation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and measured as thiobarbituric acid reactive materials, is markedly stimulated in the presence of indomethacin [1-(p-chlorobenzyl)-5-methoxy-2-methyl-3-indole acetic acid] (0.1--1.0 mM). Concurrently, indomethacin enhances the lipolysis of membrane phospholipid containing arachidonic acid but has no effect on the rate of O2 uptake in these samples. The system generates a rapidly developed chemiliminescense (CL), the intensity and rate of development of which are related to indomethacin concentration. The microsomal CL generated in the presence of indomethacin is distinct from the previously reported CL in that the time required for maximum intensity development is a matter of seconds (20--180) rather than hours. The enhanced CL is believed to be due to an energy transfer reaction whereby a high energy species transfers energy to the indomethacin molecule, which, in turn, decays via chemiluminescense. An enhanced chemiluminescense was also observed when indomethacin was added to a lipoxidase system and superoxide generating system (axanthine oxidase). Based on inhibitor studies, the rapidly developed chemiluminescense of the microsomal system requires cytochrome P-450 in addition to NADPH and coordinated iron ions. The results indicate that the CL is related to neither hydroxyl free radical nor superoxide anion formation.

Animals↗
PubMed1978

Effect of an acute dose of ethanol on rat liver microsomal mixed function oxygenase components and membrane lipid composition.

The lipid composition of rat liver microsomes was not altered in response to a single acute dose of ethanol relative to isocaloric glycerol-treated controls. Microsomal cytochrome P-450 was transiently elevated, the elevation paralleling blood ethanol levels. Microsomal NADPH oxidase was transiently elevated relative to the activity in isocaloric glycerol-treated controls.

Animals↗