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Biomedical subjects

J R Arthur

Publications and source records attributed to J R Arthur.

At least 19 recordsLinked to original sources
PubMed1992

Lipid peroxidation, antioxidant concentrations, and fatty acid contents of muscle tissue from malignant hyperthermia-susceptible swine.

Homogenates of semitendinosus muscle from malignant hyperthermia (MH)-susceptible pigs produced threefold more pentane than those from MH-resistant pigs, indicating enhanced free radical-mediated peroxidation of n-6 fatty acids. This did not reflect a deficiency in tissue antioxidants or antioxidant-enzymes but glutathione concentrations and glutathione peroxidase activities were increased in the tissue from MH-susceptible swine, consistent with an adaptive response to a sustained oxidant stress. A lower proportion of linoleic acid (18:2 n-6) in phospholipids and neutral lipids in muscle from MHS pigs indicated increased peroxidation or metabolism (desaturation and elongation). The increased oleic acid (18:1 n-9) in the MHS muscle indicated that desaturase activity was elevated in all lipid classes. The results are consistent with the hypothesis that enhanced free radical activity and lipid peroxidation contributes to the abnormalities in Ca2+ homeostasis and polyunsaturated fatty acid metabolism in MH.

Animals↗
PubMed1992

Effect of selenium deficiency on hepatic type I 5-iodothyronine deiodinase activity and hepatic thyroid hormone levels in the rat.

Selenium deficiency in rats for a period of up to 6 weeks inhibited both the production of 3,3',5-tri-iodothyronine (T3) from thyroxine (T4) (5'-deiodination) and also the catabolism of T3 to 3,3'-di-iodothyronine (5-deiodination) in liver homogenates. The hepatic stores of T3 were decreased by only 8% in selenium deficiency, despite the T3 production rate from T4 being only 7% of the rate found in selenium-supplemented rats. Hepatic glutathione S-transferase (GST) activity was increased in both hypothyroidism and selenium deficiency, but apparently by different mechanisms, since mRNA expression for this family of enzymes was lowered by hypothyroidism and increased in selenium deficiency. It is concluded that, since both T3 production and catabolism are inhibited by selenium deficiency, there is little change in hepatic T3 stores, and therefore the changes in the activity of certain hepatic enzymes, such as GST, that are found in selenium deficiency are not the result of tissue hypothyroidism.

Animals↗
PubMed1992

The role of selenium in thyroid hormone metabolism and effects of selenium deficiency on thyroid hormone and iodine metabolism.

Selenium deficiency impairs thyroid hormone metabolism by inhibiting the synthesis and activity of the iodothyronine deiodinases, which convert thyroxine (T4) to the more metabolically active 3,3'-5 triiodothyronine (T3). Hepatic type I iodothyronine deiodinase, identified in partially purified cell fractions using affinity labeling with [125I]N-bromoacetyl reverse triiodothyronine, is also labeled with 75Se by in vivo treatment of rats with 75Se-Na2SeO3. Thus, the type I iodothyronine 5'-deiodinase is a selenoenzyme. In rats, concurrent selenium and iodine deficiency produces greater increases in thyroid weight and plasma thyrotrophin than iodine deficiency alone. These results indicate that a concurrent selenium deficiency could be a major determinant of the severity of iodine deficiency.

Animals↗
PubMed1992

Selenium deficiency and type II 5'-deiodinase regulation in the euthyroid and hypothyroid rat: evidence of a direct effect of thyroxine.

Selenium deficiency in rats is characterized by elevated serum T4 and decreased serum T3 concentrations, and low liver type I (5'D-I) and brain type II (5'D-II) iodothyronine 5'-deiodinase activities. These findings are partially explained by the demonstration that type I 5'D is a selenoprotein; however, 5'D-II does not contain selenium. Since 5'D-II varies inversely with serum T4 concentrations, and serum T4 is elevated in selenium deficiency, the decreased cerebrocortical 5'D-II activity may be secondary to the increased serum T4 levels. To determine the mechanism(s) by which selenium influences 5'D-II activity, we examined the effects of altered selenium intake on brain 5'D-II levels and enzyme turnover in euthyroid and thyroidectomized rats. Rats were fed a selenium-supplemented or selenium-deficient diet for 5 weeks from weaning; half of the animals were also thyroidectomized 3 weeks before death. Selenium deficiency was confirmed by decreased liver and brain glutathione peroxidase activities. In euthyroid rats, selenium deficiency caused a 38% increase in serum T4, and 91% and 39% decreases in 5'D-I and 5'D-II, respectively, compared to those in selenium-supplemented rats. In the thyroidectomized hypothyroid rats, selenium deficiency caused a 60% decrease in 5'D-I, but had no effect on 5'D-II activity, fractional turnover of the enzyme, or the calculated enzyme synthesis rate. The lack of effect of selenium deficiency on 5'D-II levels in hypothyroid rats is consistent with the finding that 5'D-II is not a seleno-enzyme. Thus, the decrease in brain and pituitary 5'D-II activity in selenium-deficient euthyroid rats is due to the T4-dependent increase in the turnover of the enzyme polypeptide.

Animals↗
PubMed1992

Effects of selenium deficiency on thyroid hormone economy in rats.

In selenium-deficient rats, peripheral T4 to T3 conversion is markedly decreased due to the loss of the selenoprotein, type I iodothyronine 5'-deiodinase (5'D-I). Despite the marked increase in circulating T4 that results from this loss of 5'D-I, serum T3 concentrations in selenium-deficient rats remain in the normal range. To determine the physiological mechanism(s) that maintains circulating T3 when peripheral T4 to T3 conversion is impaired, we examined the interrelationships between selenium intake and the metabolism of T3 and T4 in the rat. In euthyroid rats, selenium deficiency caused the expected loss of 5'D-I, with a 52% increase in serum T4, which paralleled an increase in the T4 biological half-life. Consistent with the prolonged t1/2 of T4, short term thyroidectomy (48 h) in selenium-deficient rats failed to decrease serum T4 concentrations to the levels observed in short term thyroidectomized, selenium-supplemented rats. Short term thyroidectomy also caused an expected 33% decrease in liver 5'D-I and a 44% increase in brain type II iodothyronine 5'-deiodinase (5'D-II) activities in selenium-supplemented rats. However, in selenium-deficient rats, short term thyroidectomy did not affect 5'D-I or 5'D-II activities. In contrast to the selenium-dependent changes in circulating T4 levels, little or no change in circulating T3 concentrations occurred. There was a 20% increase in the T3 half-life in selenium-deficient rats. The serum T3 sulfate concentration was increased, and T3 deiodination was reciprocally decreased in the selenium-deficient rats. These data suggest that increased T3 sulfate generation in selenium-deficient rats may lead to greater T3 availability through enterohepatic recycling of the iodothyronine and may explain why there are only minor changes in serum T3 concentrations in selenium-deficient rats.

Animals↗
PubMed1991

The effects of selenium deficiency on hepatic type-I iodothyronine deiodinase and protein disulphide-isomerase assessed by activity measurements and affinity labelling.

We determined protein disulphide-isomerase (PDI) and iodothyronine deiodinase (ID-I) activities in liver homogenates from rats subjected to selenium (Se) and/or iodine deficiencies and food restriction. Additionally, the effects of propylthiouracil (PTU) on the enzymes were studied in vivo and in vitro. Selenium deficiency markedly inhibited ID-I activity, but had no significant effects on PDI. Iodine deficiency resulted in a 1.6-fold stimulation in ID-I and a 1.2-fold stimulation in PDI activities. ID-I was much more sensitive than PDI to the inhibitory effects of PTU both in vitro and in vivo. By using a 3,3',5'-tri[125I]iodothyronine affinity label, two major protein bands were identified when hepatic microsomal fractions from Se-sufficient rats were subjected to SDS/PAGE and autoradiography. These bands had molecular masses of 55 and 27.5 kDa, which are similar to those of PDI and ID-I respectively. Selenium deficiency resulted in the loss of the 27.5 kDa band, but did not affect the intensity of the 55 kDa band. These results are consistent with the changes in PDI and ID-I enzyme activities. Previous studies have shown that 75Se may be incorporated in vivo into the 27.5 kDa protein band. This, taken together with our observation that Se is required for the expression of ID-I and the 27.5 kDa protein band, strongly suggests that ID-I is a selenoprotein.

Affinity Labels↗
PubMed1991

Effects of smoking and vitamin E on blood antioxidant status.

Despite similar vitamin E contents, erythrocytes of smokers have an increased tendency (P less than 0.01) to peroxidize in vitro compared with those of nonsmokers. This difference is abolished by vitamin E supplementation (1000 mg alpha-tocopherol acetate/d for 14 d). The increased susceptibility to erythrocyte peroxidation in the smokers may reflect lower glucose-6-phosphate dehydrogenase (P less than 0.02) and glutathione peroxidase (P less than 0.05) activities. Smokers seem to be under a sustained oxidant stress with increased plasma-conjugated dienes (P less than 0.01) and dehydroascorbate (P less than 0.05) and decreased ascorbate (P less than 0.06) concentrations. Additionally, plasma ceruloplasmin in smokers is elevated (P less than 0.01), consistent with an acute-stress response. Plasma total cholesterol is similar in smokers and nonsmokers and is unaffected by vitamin E supplementation. Indices of sustained oxidant stress in smokers are partially ameliorated by vitamin E supplementation.

Adult↗
PubMed1991

Impairment of iodothyronine 5'-deiodinase activity in brown adipose tissue and its acute stimulation by cold in selenium deficiency.

The activity of the type II iodothyronine 5'-deiodinase enzyme in brown adipose tissue has been examined in rats-fed a selenium-deficient diet. Iodothyronine 5'-deiodinase activity was threefold lower in brown adipose tissue of deficient rats than in control animals. The activity of glutathione peroxidase, a biochemical index of selenium deficiency, was also greatly decreased in deficient animals. Cytochrome oxidase activity in brown fat was, however, unaltered by selenium deficiency. Acute exposure to cold (4 degrees C for 18 h) resulted in a substantial increase in iodothyronine 5'-deiodinase activity in brown adipose tissue of control rats, but the stimulatory effect of cold was attenuated in selenium-deficient animals. These results support the concept that the iodothyronine 5'-deiodinases are selenium-dependent enzymes, and indicate that the thermogenic response to cold may be impaired in selenium deficiency.

Adipose Tissue↗
PubMed1991

The role of selenium in thyroid hormone metabolism.

In animals, decreases in selenium-containing glutathione peroxidase activity and the resultant impairment of peroxide metabolism can account for many, but not all of the biochemical and clinical changes caused by selenium deficiency. Recently, however, type I iodothyronine 5'-deiodinase has also been shown to be a selenium-containing enzyme. This explains the impairment of thyroid hormone metabolism caused by selenium deficiency in animals with a normal vitamin E status. Since iodothyronine 5'-deiodinases are essential for the production of the active thyroid hormone 3,5,3'-triiodothyronine, some of the consequences of selenium deficiency may result from thyroid changes rather than inability to metabolise peroxides. In particular, the impaired thyroid hormone metabolism may be responsible for decreased growth and resistance to cold stress in selenium-deficient animals. A further consequence of the role of selenium in thyroid hormone metabolism is the exacerbation of some of the thyroid changes in iodine deficiency by a concurrent selenium deficiency. Selenium status may therefore have a major influence on the outcome of iodine deficiency in both human and animal populations.

Animals↗
PubMed1991

Inhibitory effects of isomers of tocopherol on lipid peroxidation of microsomes from vitamin E-deficient rats.

NADPH-induced lipid peroxidation of hepatic microsomes from vitamin E-deficient rats has been used to assess the antioxidant effectiveness of dl alpha, d alpha- and gamma-tocopherol. When the tocopherols were added in ethanol to microsomes, the degree of inhibition of formation of thiobarbituric acid reactive substances (TBARS) decreased in the order dl alpha- greater than d alpha- greater than gamma-tocopherol. This reflected the difference in the solubility of the tocopherols in the microsomes, dl alpha-tocopherol being the most soluble and gamma-tocopherol the least. Using inhibition of TBARS produced per tocopherol content in microsome as a measure of antioxidant potency, the effectiveness of the isomers was gamma- greater than d alpha- greater than dl alpha. Despite addition of pharmacological concentrations of the isomers, it was not possible to inhibit lipid peroxidation to the same levels as were found in microsomes from vitamin E sufficient animals. Use of ethanol as a vehicle may not allow optimum orientation of the tocopherols into the lipid bilayer.

Animals↗
PubMed1991

Dietary vitamin E decreases ESR signal intensity in hepatic microsomal preparations from malignant hyperthermia susceptible pigs.

On incubation with the spin trap alpha-(4-pyridyl-l-oxide)-N-tert-butylnitrone (4-POBN), a characteristic electron spin resonance (ESR) signal was produced at a greater rate in hepatic microsomal fractions from malignant hyprthermia susceptible (MHS) pigs compared with resistant (MHR) pigs. This was accompanied by increased formation of thiobarbituric acid reactive substances (TBARS). Supplementation of diets for six weeks with 235 mg alpha-tocopherol acetate/kg significantly increased microsomal vitamin E content of both pigs types. Moreover, the rate of formation of TBARS and ESR signal height of incubated microsomes from supplemented MHS pigs was decreased to that of MHR pigs. Elevated pyruvate kinase activities and TBARS concentrations in plasma of MHS pigs were also moderated by dietary vitamin E. Vitamin E supplementation may decrease the peroxidative events associated with MH.

Animals↗
PubMed1991

Inter-relationships between selenium and thyroid hormone metabolism in the rat and man.

Labelling of rat kidney microsomes in vitro with [125I]-bromoacetyl T4 produced two bands on SDS/PAGE with Mr of 55 kDa and 27.5 kDa representing protein disulphide isomerase and type I iodothyronine deiodinase (ID-I) respectively. The amount of the 55 kDa band was unchanged by selenium (Se) deficiency but the 27.5 kDa protein was markedly decreased in kidney microsomal fraction obtained from Se-deficient rats. Concurrent Se and iodine deficiency produced a significant increase in thyroid weight, plasma thyrotrophin (TSH) and a decrease in thyroidal iodine when compared with either single Se or iodine deficiency. These results suggest that ID-I is a selenoprotein and that Se deficiency can exacerbate the hypothyroidism observed in iodine deficiency. In man, blood glutathione peroxidase and blood Se levels were decreased in hyperthyroidism due to Graves' disease whilst normal levels of these analytes were found in patients treated for Graves' disease. These results suggest that thyroid status can affect Se balance rather than Se deficiency predisposes to Graves' disease.

Animals↗
PubMed1990

Hepatic iodothyronine 5'-deiodinase. The role of selenium.

Selenium (Se) deficiency decreased by 8-fold the activity of type 1 iodothyronine 5'-deiodinase (ID-I) in hepatic microsomal fractions from rats. Solubilized hepatic microsomes from rats injected with 75Se-labelled Na2SeO3 4 days before killing were found by chromatography on agarose gels to contain a 75Se-containing fraction with ID-I activity. PAGE of this fraction under reducing conditions, followed by autoradiography, revealed a single 75Se-containing protein (Mr 27,400 +/- 300). This protein could also be labelled with 125I-bromoacetyl reverse tri-iodothyronine, an affinity label for ID-I. The results suggest that hepatic ID-I is a selenoprotein or has an Se-containing subunit essential for activity.

Animals↗
PubMed1990

The changes in hepatic enzyme expression caused by selenium deficiency and hypothyroidism in rats are produced by independent mechanisms.

Selenium (Se) deficiency for 5 weeks in rats produced changes in the activity of a number of hepatic, renal and plasma enzymes. In animals whose food intake was restricted to 75% of normal for 2 weeks, Se deficiency produced significant increases in the activity of hepatic cytosolic 'malic' enzyme and mitochondrial alpha-glycerophosphate dehydrogenase (GPD), two enzymes that are particular sensitive to the thyroid-hormone concentrations in tissue. Propylthiouracil-induced hypothyroidism produced significant decreases in 'malic' enzyme and GPD activities. The effect of hypothyroidism on the activity of 'malic' enzyme, GPD and other enzymes studied in liver and plasma was often opposite to that seen in Se deficiency. Glutathione S-transferase (GST) activity was increased by both Se deficiency and hypothyroidism, but in hypothyroid animals further significant increases in GST were produced by Se deficiency. These data suggest that the changes in enzyme expression observed in Se deficiency are not caused by decreased tissue exposure to thyroid hormones.

Animals↗
PubMed1990

Spin trapping of free radicals and lipid peroxidation in microsomal preparations from malignant hyperthermia susceptible pigs.

Microsomes were prepared from livers of malignant hyperthermia susceptible (MHS) or resistant (MHR) pigs. On incubation with the spin trap alpha-(4-pyridyl-l-oxide)-N-tert-butylnitrone (4-POBN), the microsomes from MHS pigs produced a characteristic electron spin resonance (ESR) signal at a greater rate than those from MHR pigs. Increased formation in the incubations of thiobarbituric acid reactive substances (TBARS) by the microsomes of the MHS pigs indicated an enhanced susceptibility to free radical-mediated lipid peroxidation. These results provide further evidence that MHS pigs have an antioxidant abnormality which may contribute to the fatal MH response. However the nature of the abnormality is unclear. The enhanced formation of unstable free radicals and indices of lipid peroxidation was not due to decreased vitamin E concentration or glutathione peroxidase activity in the microsomes. Furthermore, fatty acid profiles were similar in microsomes from MHS and MHR pigs indicating similar amounts of potential substrate for TBARS formation.

Animals↗
PubMed1990

Anaemia and changes in erythrocyte morphology associated with copper and selenium deficiencies and dietary restriction in rats.

Both selenium and copper deficiencies in rats caused morphological changes in erythrocytes but only copper deficiency resulted in anaemia. Similar but less severe morphological changes occurred when rats consuming selenium- and copper-adequate diets had their food intake restricted to that of the copper-deficient animals. Since selenium deficiency did not affect the severity of changes due to copper deficiency this suggests that alterations of erythrocyte morphology may not be entirely due to impaired functions of selenium and copper in cell antioxidant systems. Thus, erythrocyte structure was sensitive to several dietary changes and such alterations are probably independent of the anaemia induced by copper deficiency. This possibility should be considered when changes in erythrocyte morphology are attributed to copper or selenium deficiency in animals which also have a restricted food intake.

Anemia↗