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Biomedical subjects

D V Parke

Publications and source records attributed to D V Parke.

At least 127 records · Page 7Linked to original sources
PubMed1982

Selective inhibition of the safrole-induced mixed-function oxidase activities by 9-hydroxyellipticine.

Intraperitoneal administration of 9-hydroxyellipticine, a specific cytochrome P-448 inhibitor, inhibited 3-methylcholanthrene-induced cytochrome P-448 activity (ethoxyresorufin O-deethylase, biphenyl 2-hydroxylase) and formation of the safrole carbene ligand complex with this cytochrome, but did not inhibit phenobarbital-induced cytochrome P-450 activity (ethyl-morphine N-demethylase) or formation of the safrole carbene ligand complex with this cytochrome. Biphenyl displaced the 9-hydroxyellipticine ligand from cytochrome P-448 leading to increased free cytochrome, but with no corresponding increase in mixed-function oxidase activity when biphenyl was used as substrate. It is concluded that following dissociation of the ligand complex, 9-hydroxyellipticine, which also exhibits type I binding, competes with biphenyl for the substrate binding site. Administration of 9-hydroxyellipticine to safrole-pretreated rats inhibited the cytochrome P-448-catalysed activity, but had no effect on the cytochrome P-450-catalysed activity. These results indicate that safrole induces a mixture of cytochromes P-450 and P-448 rather than a single novel haemo-protein. The type I substrate biphenyl displaced both the safrole carbene and the 9-hydroxyellipticine ligands from cytochrome P-448 resulting in increased free cytochrome. Displacement of the safrole carbene ligand was accompanied by increased mixed-function oxidase activity but, in contrast, displacement of the 9-hydroxyellipticine ligand resulted in no increase in mixed-function oxidase activity.

Alkaloids↗
PubMed1982

Mechanisms of chemical toxicity--a unifying hypothesis.

Most cases of chemical toxicity involve one or both of the fundamental pathological processes of "acute lethal injury" and "autoxidative cellular injury." The process of "acute lethal injury" by which toxic chemicals interfere with cellular energy metabolism, leading ultimately to cell death and tissue necrosis, is well known and reasonably understood. Inhibition of glycolysis, mitochondrial respiration, or oxidative phosphorylation, resulting in lack of ATP synthesis or inhibition of ATPase and other enzymes, leads to decreased efficiency of the sodium pump, hydropic degeneration, lipid accumulation, and eventually cell death. Less well known are the mechanisms whereby toxic chemicals initiate autoxidation, leading to "autoxidative cellular injury," disrupting cell membranes, and resulting in increased autophagocytosis, cell death, and mutations. Many reactive intermediates of toxic chemicals are electrophiles, free radicals, or free-radical generators, which may potentiate the toxicity of tissue oxygen, depleting intracellular glutathione and biological antioxidants, resulting in membrane damage, impairment of the calcium pump, cell death, and damage to DNA. The mechanisms of oxygen toxicity and chemical-mediated oxygen toxicity are discussed, with particular reference to the microsomal mixed-function oxidase system and its role in the detoxication and activation of environmental chemicals. The dependence of tissue oxygen concentration, the rates of oxidative activation of chemicals, and the extents of autoxidative cellular injury on the size of the animal species is considered, and the importance of this to the scientific evaluation of chemical toxicity is discussed.

Animals↗
PubMed1982

Metabolic activation of dimethylnitrosamine to mutagens: role of cytochromes P-450 and P-448.

Pretreatment of hamsters with phenobarbitone, 3-methylcholanthrene and Arochlor 1254 induced the hepatic microsomal mixed function oxidases, yet decrease the efficiency of activation of dimethylnitrosamine (DMN) to intermediates mutagenic to the Salmonella typhimurium strain TA-100. Furthermore, no correlation was obtained between cytochrome P-450 content, microsomal demethylation of DMN and its activation to mutagens. These results indicate that the demethylation of DMN by the mixed-function oxidases is not the rate-limiting step in the metabolic activation of the carcinogen to mutagen(s), and that other microsomal or soluble enzymes may be involved.

Animals↗
PubMed1982

The mutagenicity of 9-hydroxyellipticine and its induction of cytochrome P-448 activity in rat liver microsomes.

Administration of a single dose of the inhibitor of the hepatic mixed function oxidases, 9-hydroxyellipticine (9-OHE), resulted in a marked increase in the cytochrome P-448 catalysed activities of ethoxyresorufin O-deethylase, biphenyl 2-hydroxylase and activation of benzo[a]pyrene to mutagens. In contrast there was no effect on the cytochrome P-450 catalysed benzphetamine N-demethylase activity. The inductive effect was prevented by simultaneous administration of the protein synthesis inhibitors cycloheximide and actinomycin D. It is concluded that 9-OHE may also act as an inducer of the hepatic microsomal mixed function oxidases, selectively inducing the synthesis of cytochrome P-448. Therefore, 9-OHE, like other inhibitors of this enzyme system, exhibits a biphasic effect, its inhibitory phase being followed by one of enzyme induction. 9-OHE was a direct mutagen in the Salmonella typhimurium strains TA 98 and TA 100.

Alkaloids↗
PubMed1982

Elimination of glyceryl trinitrate: effects of sex, age, species and route of administration.

1 Orally administered glyceryl trinitrate to rats undergoes extensive first pass metabolism leading to low bioavailability. 2 Sex differences in the plasma elimination of glyceryl trinitrate were seen in the rat, the female exhibiting the longer plasma half-life. No sex differences in this respect were detected in the rabbit. 3 The plasma half-life of glyceryl trinitrate was longer and the volume of distribution larger, in older animals. 4 The plasma elimination of glyceryl trinitrate was different in various animal species. There was a good correlation between plasma half-life and animal bodyweight.

Aging↗
PubMed1982

Biochemical differences in human glomerular basement membrane related to diabetes and age.

Preparations of glomerular basement membrane from diabetic and young and aged normal subjects have been isolated and purified and the component carbohydrates and amino acids quantitatively determined. Diabetic membrane preparations, compared with membranes from young normal subjects, show significant increases in total hexoses, mannose, and galactose and decreases in sialic acid and glucose; the component amino acids show increases in hydroxylysine, proline, and glycine and decreases in lysine, histidine, and leucine. Basement membrane preparations from aged normals show changes in component carbohydrates and amino acids similar to, but not as great as, those seen in the diabetics.

Adolescent↗
PubMed1982

Metabolism and excretion of a chromone carboxylic acid (FPL 52757) in various animal species.

1. The disposition of the chromone carboxylic acid (FPL 52757) in several species has been investigated. The compound is extensively metabolized by hydroxylation in rat, mouse, ferret, squirrel monkey, cynomolgus monkey, rabbit, hamster, stumped-tailed macaque and baboon (e.g. 50-100% in rat, cynomolgus monkey and squirrel monkey). 2. The plasma clearance of the chromone in rat, rabbit and squirrel monkey was 138, 44 and 59 ml/kg per h respectively. Plasma clearance by the dog was slower (13 ml/kg per h) and due mainly to elimination of unchanged compound. 3. As the dog is particularly susceptible to FPL 52757-induced hepatotoxicity the parent compound may be responsible. Species which clear the compound rapidly compared with the dog did not show a hepatotoxic response. 4. Although metabolism occurs in man the clearance is still slow (15 ml/kg per h) and may be one reason for human susceptibility to a mild hepatotoxic effect with the compound.

Animals↗
PubMed1982

The mechanism of hepatotoxicity of a chromone carboxylic acid (FPL 52757) in the dog.

1. The chromone carboxylic acid (6,8-diethyl-5-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylic acid) is hepatotoxic in dogs (at 40 mg/kg per day). This toxicity did not appear to be mediated by a reactive metabolite, as the compound was not metabolized by the dog, and phenobarbitone pretreatment (20 mg/kg per day) protected rather than potentiated. 2. Other studies in the dog showed that the chromone caused increases in the biliary excretion of alkaline phosphatase (17-fold), gamma-glutamyl-transpeptidase (9-fold), and 5'-nucleotidase (13-fold) which paralleled the biliary concentration of the drug (up to 1.3 mg/ml) and was accompanied by a reduction in bile flow. 3. The excretion of the chromone into the biliary tract of the dog was shown to be saturable, and therefore high hepatocellular concentrations of the drug and subsequent liver damage could result. 4. The toxicity of the chromone when administered to rat by retrograde biliary infusion, and the lysis of erythrocytes in vitro, are related to detergent properties of the drug and add confirmatory evidence for a mechanism of toxicity in the dog. 5. It is concluded that the chromone itself is responsible for the toxicity in the dog due to its detergent properties causing damage to the hepatobiliary tract. The protection by phenobarbitone and also by methionine may have been due to an increased bile flow reducing biliary concentrations.

Animals↗
PubMed1982

Hepatic microsomal drug metabolism in the pregnant rat.

1. Hepatic microsomal drug metabolism determined with the substrates aniline (p-hydroxylation), ethylmorphine (N-demethylation) and p-nitrobenzoic acid (reduction), decreased during gestation in the rat to 53-73% of non-pregnant control levels by day 20 of gestation. 2. Enzyme activity remained low at one day post-partum, but had returned to control non-pregnant levels by five days post-partum. 3. The total capacity of the liver to metabolize drugs remained unchanged or increased because liver weight was increased by up to 40% during pregnancy. 4. Changes in drug metabolism were not related to alterations in the concentration, substrate-induced binding affinity (Ks) or maximal spectral change (delta Amax) of cytochrome P-450. 5. Alterations in hepatic drug metabolism are possibly mediated via changes in microsomal phospholipids and/or the cytochrome P-450 spin-state equilibrium as as pregnancy was associated with a decrease in (a) microsomal total phospholipids, (b) the phosphatidylcholine to phosphatidylethanolamine ratio and (c) the high-spin form of ferricytochrome P-450.

Aniline Hydroxylase↗
PubMed1981

Serum "prealbumin" as an index of liver function in human hepatobiliary disease.

Serum prealbumin concentrations have been studied, by a quantitative immunological procedure, in patients with secondary carcinoma of the liver, chronic active hepatitis, alcoholic hepatitis, cryptogenic cirrhosis, obstructive jaundice, inflammatory bowel disease, and myocardial infarction. The results showed that prealbumin concentration is significantly decreased when liver function is impaired. In diseases not associated with liver damage the concentrations of prealbumin were within the normal range. The advantage of this biochemical procedure is that serum prealbumin concentration is a true index of liver function, whereas serum enzyme activities signify only the degree of hepatocellular damage, which may not always quantitatively reflect liver function. Determination of serum prealbumin is therefore valuable in the diagnosis of liver disease and in the monitoring of treatment.

Biliary Tract Diseases↗
PubMed1981

Glycylprolyl-p-nitroanilidase in hepatobiliary disease.

The serum activity of glycylprolyl-p-nitroanilidase (GPN) has been compared with isocitrate dehydrogenase and with alanine and aspartate aminotransferases in patients with hepatobiliary diseases, myocardial infarction and chronic inflammatory bowel disease. Serum GPN was markedly increased in all hepatobiliary diseases, especially secondary carcinoma and chronic alcoholic hepatitis, but no abnormal values were seen in patients with chronic inflammatory bowel disease. Slightly elevated GPN activities were noticed in a few cases of myocardial infarction. It is suggested that serum GPN would be useful for monitoring hepatic function, especially in the clinical trials of new drug.

Alanine Transaminase↗
PubMed1981

The influence of high dietary zinc on tissue disposition and urinary excretion of cadmium, zinc, copper and iron after repeated parenteral administration of cadmium to rats.

The administration of a high dietary supplement of zinc sulphate (2000 ppm) to rats for 28 days produced no effect upon growth rate of the animals but caused in increased food intake. The supplement had no effect upon the reduction of growth rate caused by the daily injection of cadmium chloride (1.5 mg/kg). Zinc-supplemented animals showed an increased accumulation of zinc in the liver and kidney, plasma zinc levels were significantly increased and there was an elevated excretion of zinc in the urine compared to control animals. Cadmium-treated, zinc-supplemented animals had a higher concentration of cadmium in the liver compared to animals treated only with cadmium. The high dietary zinc did not interfere with tissue or plasma concentration of copper and iron, nor did it influence the cadmium-induced changes in these metals. There was some indication however of a decreased urinary excretion of copper.

Animals↗
PubMed1981

The acute and subacute effects of cadmium an calcium homeostasis and bone trace metals in the rat.

The effect of acute and subacute administration of cadmium chloride on calcium homeostasis and the trace metal content of the bone was investigated in the male rat. A single subcutaneous injection of cadmium chloride (1.5 mg Cd++/kg) produced a decreased plasma concentration of calcium and a decrease in the femur concentration of both calcium and zinc. repeated administration of cadmium chloride (1.5 mg Cd++/kg) daily, for 28 days) caused a marked hypocalciuria that persisted throughout the period of cadmium treatment. There was an accompanying increased excretion of alkaline phosphatase into the urine, and plasma inorganic phosphate was also elevated in these animals. Both of these effects are considered to be evidence of kidney damage. A possible mechanism for this cadmium-induced effect may involve a disturbance of the renal biotransformation of vitamin D, and decreased bioavailability of the essential trace metals due to metallothionein synthesis and excessive loss into the urine.

Alkaline Phosphatase↗