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Biomedical subjects

P M Coates

Publications and source records attributed to P M Coates.

At least 73 records · Page 4Linked to original sources
PubMed1985

Genetic deficiency of medium-chain acyl coenzyme A dehydrogenase: studies in cultured skin fibroblasts and peripheral mononuclear leukocytes.

Medium-chain acyl coenzyme A (CoA) dehydrogenase deficiency was demonstrated in fibroblasts and/or mononuclear leukocytes from 14 patients, most of whom initially presented early in childhood with a Reye-like syndrome associated with hypoketotic hypoglycemia, dicarboxylic aciduria, and low levels of plasma carnitine. Parents of these patients had intermediate levels of medium-chain acyl CoA dehydrogenase activity, consistent with their being heterozygous for an autosomal recessive trait. All patients had normal levels of long-chain acyl CoA dehydrogenase activity, but had reduced short-chain acyl CoA dehydrogenase activity. Fatty acid oxidation was examined in cultured fibroblasts from five of the patients, using a series of 14C-labeled fatty acids of different chain length (palmitic, octanoic, and butyric). Oxidation of [1-14C]-octanoic acid was less than 20% of control levels: [1-14C], [6-14C]-, [16(14)C]-, and [14C(U)]-palmitic acid oxidation rates were 88, 51, 13, and 42% of control rates, respectively. [1-14C]-butyric acid was oxidized normally. These data extend our previous findings of medium-chain acyl CoA dehydrogenase deficiency in liver tissue from three of these patients. They demonstrate the value of cultured fibroblasts and leukocytes in the diagnosis and evaluation of inherited disorders of fatty acid oxidation.

Acyl-CoA Dehydrogenase, Long-Chain↗
PubMed1984

Effect of diabetes and insulin therapy on human mononuclear leukocyte lysosomal acid lipase activity.

Acid lipase activity was measured in mononuclear leukocytes obtained from 18 newly diagnosed type-I diabetics and from six newly diagnosed type-II diabetics before and five to ten days after the initiation of insulin therapy. Using either 4-methylumbelliferyl oleate or cholesteryl[1-14C]oleate as substrate for the enzyme assays, acid lipase activity in the diabetics was not found to be significantly different from that in the controls, significantly less (P less than 0.05) after insulin therapy in type-I diabetics, and unchanged following treatment in the type-II patients. These results differ from those found in previous studies of acid lipase activity in type-II diabetics, in whom insulin therapy evoked a doubling of enzyme activity. The effect of insulin treatment on the activity of lysosomal acid lipase requires further evaluation.

Adolescent↗
PubMed1983

Effect of early nutrition on serum cholesterol levels in adult rats challenged with high fat diet.

Early exposure to cholesterol-enriched, high fat diets has been reported to affect serum cholesterol levels in adult rats. In this study, we investigated the role of dietary fat alone, without cholesterol, by feeding to pregnant rats (from day 18 of gestation) experimental diets containing either high fat (corn oil), low sucrose (HF) or low fat, high sucrose (HS). After birth, mothers and pups were fed the diets until weaning (30 days), when serum cholesterol levels were the same in both groups of pups. Animals were fed stock diet until 7 months. At that time, half the animals from each original group (HF or HS) were challenged with HF diet for 3 days; the other half were fed stock diet. There was no significant difference in serum cholesterol between HF and HS animals fed stock diet: HF, 73 +/- 7 mg/dl (n = 11); HS, 80 +/- 19 (6); P greater than 0.25. Animals originally fed HF diet significantly raised serum cholesterol in response to late HF challenge (140 +/- 31 mg/dl, n = 10, P less than 0.001 vs. stock fed); the original HS-fed group did not (93 +/- 7 mg/dl, n = 5, P greater than 0.19). Early exposure to HF diet, even without cholesterol, could evoke a hypercholesterolemic response in adulthood following challenge by brief exposure to HF diet.

Animals↗
PubMed1983

Influence of perinatal nutrition on hepatic drug metabolism in the adult rat.

Pregnant rats were fed high-fat (HF, 35% calories) or low-fat (LF, 5% calories) diet from 18 days of gestation to the end of the suckling period. Thereafter, male progeny were fed stock diet for 6 months, then sacrificed or challenged for 3 days with HF diet. There were no immediate posttreatment effects at 30 days of age on liver microsomal cytochrome P-450 or b5, aminopyrine (AP) N-demethylase or benzo(a)pyrene (BP) hydroxylase. At 7 months, cytochrome P-450 was lower in LF-fed than in HF-fed animals. High-fat challenge reduced cytochrome P-450 and cytochrome b5 content in both groups, AP N-demethylase only in LF animals and BP hydroxylase only in HF animals. These differential effects of perinatal exposure to diet on the later response of microsomal mixed-function oxidases to fat challenge suggest that early dietary experience may regulate the pattern of drug metabolism in adult life.

Aminopyrine N-Demethylase↗
PubMed1983

Medium-chain acyl-CoA dehydrogenase deficiency in children with non-ketotic hypoglycemia and low carnitine levels.

Three children in two families presented in early childhood with episodes of illness associated with fasting which resembled Reye's syndrome: coma, hypoglycemia, hyperammonemia, and fatty liver. One child died with cerebral edema during an episode. Clinical studies revealed an absence of ketosis on fasting (plasma beta-hydroxybutyrate less than 0.4 mmole/liter) despite elevated levels of free fatty acids (2.6-4.2 mmole/liter) which suggested that hepatic fatty acid oxidation was impaired. Urinary dicarboxylic acids were elevated during illness or fasting. Total carnitine levels were low in plasma (18-25 mumole/liter), liver (200-500 nmole/g), and muscle (500-800 nmole/g); however, treatment with L-carnitine failed to correct the defect in ketogenesis. Studies on ketone production from fatty acid substrates by liver tissue in vitro showed normal rates from short-chain fatty acids, but very low rates from all medium and long-chain fatty acid substrates. These results suggested that the defect was in the mid-portion of the intramitochondrial beta-oxidation pathway at the medium-chain acyl-CoA dehydrogenase step. A new assay for the electron transfer flavoprotein-linked acyl-CoA dehydrogenases was used to test this hypothesis. This assay follows the decrease in electron transfer flavoprotein fluorescence as it is reduced by acyl-CoA-acyl-CoA dehydrogenase complex. Results with octanoyl-CoA as substrate indicated that patients had less than 2.5% normal activity of medium-chain acyl-CoA dehydrogenase. The activities of short-chain and isovaleryl acyl-CoA dehydrogenases were normal; the activity of long-chain acyl-CoA dehydrogenase was one-third normal. These results define a previously unrecognized inherited metabolic disorder of fatty acid oxidation due to deficiency of medium-chain acyl-CoA dehydrogenase.

Acyl-CoA Dehydrogenase, Long-Chain↗
PubMed1983

Influence of dietary carbohydrates (alpha-saccharides) on hepatic drug metabolism in male rats.

Young male rats (SD, CD strain) were fed semisynthetic isocaloric diets ad lib for different time periods (3,7,14, or 28 days); both carbohydrate (starch or sucrose) content and fat content were varied. High starch (HST) diet contained starch (73% of calories), corn oil (6%), and casein (21%); low starch (LST) diet contained 6, 73, and 21% of calories, respectively. In high sucrose (HS) or low sucrose (LS) diets, starch was replaced by sucrose. Rats fed LST and LS diets had decreased liver weight compared to those fed HST and HS diets, while liver microsomal protein content (mg/gm liver) was the same in all groups. Significant decreases in microsomal cytochrome P-450 from the basal level were observed in all diets over the period of experimental feeding. This decrease was more prominent with HST or HS diets compared to LST or LS dietary groups. HS diet feeding produced this decrease in cytochrome P-450 levels by 3 days; however, animals on HST diet required 7 days of feeding before they experienced a similar decrease in cytochrome P-450 levels. At 14 days, HST-fed animals had 52% lower liver microsomal cytochrome P-450 than did LST-fed animals. HS-fed animals had 36% lower cytochrome P-450 than LS-fed at 28 days. Similar results were observed for dietary effects on cytochrome b5. Aminopyrine demethylase activity decreased steadily on all diets. p-Nitrophenol glucuronidation was significantly increased in all dietary groups after 2 weeks of diet feeding. These results suggest that dietary carbohydrates and fat (particularly the relative quantities of carbohydrate and fat) may significantly influence the hepatic drug-metabolizing enzymes. It is speculated that these changes may occur due to alteration in the phospholipid composition of endoplasmic reticulum or by limiting the supply of cofactor(s) necessary for optimal mixed function oxidation and conjugation.

Aminopyrine N-Demethylase↗
PubMed1982

Hormone-sensitive lipase in human adipose tissue, isolated adipocytes, and cultured adipocytes.

Employing a perifusion technique, the activity of hormone-sensitive lipase (HSL) in human adipose tissue and isolated adipocytes was found to be significantly stimulated by 5 microM epinephrine (5-fold. P less than 0.001) or 0.5 mM theophylline (2-fold, P less than 0.03). The stimulatory effect of both, however, was not cumulative; instead, theophylline appeared to blunt the epinephrine effect. The two effectors together produced a 3-fold increase in activity over basal (P less than 0.01). Basal lipolysis was highly and significantly correlated with epinephrine and/or theophylline stimulated lipolysis in the tissue as well as in the isolated cells. The activity of the enzyme was examined in cultured human adipocytes using a cell-free system. The basal activity of HSL in the 20,000 X g supernatant (S20) fraction of cultured cells grown in fat-enriched medium was significantly higher than the value in the same fraction of cells grown in regular medium (6.06 +/- 1.49 versus 2.78 +/- 0.89 nmole glycerol/min/mg protein, mean +/- S.D., P less than 0.01), an was similar in the S20 fractions of cells grown in the enriched medium and the original tissue (6.06 +/- 1.49 versus 5.44 +/- 2.73 nmole glycerol/Min/mg protein, mean +/- S.D., P greater than 0.83). When the tissue and cells were stimulated in vitro before fractionation, the HSL activity in the S20 fraction of the original tissue increased 4-fold over basal (P less than 0.001), whereas that in the cultured cells increased 2-fold (P less than 0.01) regardless of the culture medium employed. In the S20 fractions derived from basally incubated samples, but not in those derived from the epinephrine-stimulated samples, the HSL enzyme was slightly but significantly (P less than 0.002) activated by exogenous addition of ATP, cyclic AMP, and protein kinase. The data suggest that the activity of HSL is retained in cultured human adipocytes and could be enhanced under conditions of culture which favor lipid accumulation and adipose conversion.

Adipose Tissue↗
PubMed1982

Effect of thyroid hormones on human mononuclear leukocyte lysosomal acid lipase activity.

Lysosomal acid lipase (LAL), the enzyme which hydrolyzes lipoprotein cholesteryl esters, is under thyroid hormone regulation in experimental animals. To evaluate whether human LAL is also under thyroid regulation, we measured mononuclear leukocyte LAL activity in 31 hypothyroid, hyperthyroid, and euthyroid children under treatment. LAL activity was positively correlated with serum T3 and serum T4 levels, and was significantly higher in hyperthyroid children than in those who were hypothyroid. In another study, 5 adult euthyroid males were given 50 micrograms L-T3 every 8 h for 4 days. Their LAL activities increased significantly after treatment. The data suggest that LAL activity in man, as in experimental animals, is influenced by thyroid hormone status. Hormonal control of LAL activity may be important in the regulation of human cholesterol metabolism.

Adolescent↗
PubMed1979

Acid lipase activity of human lymphocytes.

Acid lipase activity was examined in human leukocytes using 4-methylumbelliferyl esters in a fluorimetric assay. Mononuclear leukocytes had 10--15 times the acid lipase activity of polymorphonuclear leukocytes. The enzyme activity was highest using the oleate ester of 4-methylumbelliferone at pH 4.0, in the presence of L-alpha-phosphatidylcholine and taurodeoxycholic acid (sodium salt). Acid lipase activity was inhibited by diethylaminoethoxyhexestrol, sodium chloride and fluoride, potassium chloride, calcium chloride and albumin, but was unaffected by diethyl p-nitrophenyl phosphate or sulphydryl reagents. There were at least two forms of acid lipase activity: one (A form) was sensitive to heart inactivation (56 degrees C) and corresponded to the enzyme deficient in patients with Wolman's disease; the other (B form) was resistant to heat inactivation and corresponded to the residual enzyme activity found in Wolman's disease.

Bile Acids and Salts↗
PubMed1979

I-cell disease: intracellular desialylation of lysosomal enzymes using an influenza virus vector.

It has been proposed that I-cell disease results from a primary deficiency of acid neuraminidase activity. Infection by influenza virus of fibroblasts from a patient with I-cell disease resulted in the production of abundant intracellular alpha2-3 neuraminidase activity. Despite electrophoretic evidence of desialylation of intracellular and fibroblast-secreted arylsulfatase (EC 3.1.6.1) and beta-hexosaminidase (EC 3.2.1.30) from the infected cells, there was no consequent alteration of the abnormal distribution of beta-hexosaminidase activity between the intracellular spaces characteristic of I-cell disease. This suggests that deficiency of alpha2,3 neuraminidase activity is not the primary biochemical defect in I-cell disease.

Arylsulfatases↗
PubMed1978

Prenatal diagnosis of Wolman disease.

Two pregnancies at risk for Wolman disease were monitored by assay and electrophoresis of acid lipase in cultured amniotic-fluid cells. Cells from patient 1 had 5% of control levels of acid lipase, using 14C-triolein as substrate; however, when artificial substrates (esters of 4-methylumbelliferone and p-nitrophenol) were used to measure acid lipase, these cells had 30% of control levels. Electrophoresis of cell extracts revealed the absence of the A form of acid lipase, consistent with the diagnosis of Wolman disease. Analysis of fetal tissues following prostaglandin termination of this pregnancy confirmed the diagnosis. Assay of fetal-skin fibroblasts with 14C-triolein, as well as with artificial substrates, showed marked deficiency of acid lipase activity. Electrophoresis of fetal-tissue extracts also demonstrated the absence of the A form of acid lipase. Amniotic-fluid cells from patient 2 showed normal levels of acid lipase with all substrates tested; the electrophoretic pattern of acid lipase was normal. The results suggest that the prenatal diagnosis of Wolman disease be made using the radioassay of acid lipase and/or electrophoresis.

Acetylglucosaminidase↗
PubMed1978

Neonatal presentation of I-cell disease.

Two patients are described in whom the diagnosis of I-cell disease was established in early infancy. These patients lacked many of the clinical and radiographic features described in other children with this disorder. Differences between the neonatal and early childhood presentation of ICD are discussed.

Hip↗
PubMed1978

Acid and neutral lipases of cultured adipocytes of infants and children.

In order to determine whether the mobilization of intracellular triglycerides observed in cultured human adipocytes is associated with changes in the activities of acid and neutral lipases, the activities of both enzymes were measured weekly on cultured adipocytes for several months. The activity of acid lipase was initially very low, but rose to levels 40 times the original activity within 3 months. The activity of neutral lipase decreased rapidly within the first 2-4 weeks and remained at approximately 25% of original levels thereafter.

Adipose Tissue↗
PubMed1977

Characteristics and postnatal development of the acid lipase activity of the rat small intestine.

Acid lipase was identified in the rat small intestine by using esters of 4-methylumbelliferone as substrates. Maximum activity towards the oleate ester was found at pH 4.0. In adult animals, the activity of acid lipase exhibited both latency and sedimentability, indicating a lyosomal localization. The activity of acid lipase was practically the same along the height of the villus, thus paralleling the distribution of acid beta-galactosidase. In adult rats, the activity of acid lipase in proximal (jejunum) and middle (mid-jejunum) sections of the small intestine was practically the same and exceeded the activity in the distal (ileum) section by a factor of 2. In suckling rats, the activity of the enzyme in the mid-jejunum exceeded that in the jejunum and ileum by 2.5- and 1.5-fold respectively. During postnatal development, the acid lipase activity of the mid-jejunum showed a peak between days 10 and 15, at which time it exceeded the adult mid-jejunum activity by 5--6-fold.

Aging↗