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Biomedical subjects

F Nicol

Publications and source records attributed to F Nicol.

At least 55 records · Page 3Linked to original sources
PubMed1993

Effects of combined iodine and selenium deficiency on thyroid hormone metabolism in rats.

This paper compares the effects of combined iodine and selenium deficiency, of single deficiencies of these trace elements, and of no deficiency on thyroid hormone metabolism in rats. In rats deficient in both trace elements, thyroidal triiodothyronine (T3), thyroidal thyroxin (T4), thyroidal total iodine, hepatic T4, and plasma T4 were significantly lower, and plasma thyroid-stimulating hormone (TSH) and thyroid weight were significantly higher than in rats deficient in iodine alone. Plasma and hepatic T3 concentrations were similar in the dietary groups. Hepatic type I iodothyronine deiodinase (ID-I) activity was inhibited by selenium deficiency irrespective of the iodine status. Type II deiodinase (ID-II) activity in the brain was significantly higher and in pituitary, significantly lower in combined deficiency than in iodine deficiency alone. These data show that selenium can play an important role in determining the severity of the hypothyroidism associated with iodine deficiency.

Animals↗
PubMed1993

The role of thyroidal type-I iodothyronine deiodinase in tri-iodothyronine production by human and sheep thyrocytes in primary culture.

We have studied the origin of tri-iodothyronine (T3) secreted by human and sheep thyrocytes in primary culture and also the expression of type-I thyroidal iodothyronine deiodinase (ID-I) in the thyroid and liver of man and various other animals. Inhibitors of ID-I reduced T3 secretion from human but not sheep thyrocytes. In contrast, inhibitors of de-novo thyroid hormone synthesis reduced both thyroxine (T4) and T3 production in sheep thyrocytes, but had no effect on the T3 secreted by human thyrocytes. Human thyrocytes did not produce T4 under the culture conditions used, although some endogenous T4 was present in the cells following their isolation. Although thyrotrophin (TSH) stimulated T3 production in both human and sheep thyrocytes, iodine in the form of potassium iodide was only essential for T3 and T4 production by the sheep cells. Although 125I from Na125I was incorporated into T3 and T4 in TSH-stimulated sheep thyrocytes, no 125I incorporation into T3 or T4 was detected in TSH-stimulated human thyrocytes. Using activity measurements and affinity labelling, ID-I was present in the livers of all species studied, but ID-I could not be detected in thyroid tissue from cattle, pigs, sheep, goats, rabbits, deer or llamas. In contrast, thyroid tissue from man, mice, guinea-pigs and rats had significant ID-I activity and expressed an affinity-labelled protein with a molecular mass of approximately 28.1 kDa on SDS-PAGE. These data show that under the culture conditions used, sheep thyrocytes produced T3 by de-novo synthesis, whilst human thyrocytes produced T3 by deiodination of endogenous T4. We conclude that thyroidal ID-I shows marked species difference in its expression and that, in those species which express the enzyme (man, mice, guinea-pigs and rats, in this study), it appears that it may make an important contribution to thyroidal T3 production.

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↗
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

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

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

The effects of selenium depletion and repletion on the metabolism of thyroid hormones in the rat.

Rats were fed selenium-deficient (less than 0.005 mg selenium/kg) or selenium-supplemented diets (0.1 mg selenium/kg, as Na2SeO2) for up to five wks from weaning to assess the effects of developing selenium deficiency on the metabolism of thyroid hormones. Within two wks 3:5,3'-triiodothyronine (T3) production from thyroxine (T4) in liver homogenates from selenium-deficient rats was significantly lower compared with the activity in liver homogenates from selenium-supplemented rats. This decreased activity was probably responsible, in part, for the higher T4 and lower T3 concentrations in plasma from the selenium-deficient rats after 3, 4, and 5 weeks of experiment. Repletion of selenium-deficient rats with single intra-peritoneal injections of 200 micrograms selenium/kg body wt. (as Na2SeO3) 5 days before sampling reversed the effects of the deficiency on thyroid hormone metabolism and significantly increased liver and plasma glutathione peroxidase activities. However a dose of 10 micrograms selenium/kg body wt given to rats of similar low selenium status had no effect on thyroid hormone metabolism or glutathione peroxidase activity but did reverse the increase in hepatic glutathione S-transferase activity characteristic of severe selenium deficiency. Imbalances in thyroid hormone metabolism are an early consequence of selenium deficiency and are probably not related to changes in hepatic xenobiotic metabolizing enzymes associated with severe deficiency.

Animals↗
PubMed1989

Inhibition of type I and type II iodothyronine deiodinase activity in rat liver, kidney and brain produced by selenium deficiency.

Selenium deficiency for periods of 5 or 6 weeks in rats produced an inhibition of tri-iodothyronine (T3) production from added thyroxine (T4) in brain, liver and kidney homogenate. This inhibition was reflected in plasma T4 and T3 concentrations, which were respectively increased and decreased in selenium-deficient animals. Although plasma T4 levels increased in selenium-deficient animals, this did not produce the normal feedback inhibition on thyrotropin release from the pituitary. Selenium deficiency was confirmed in the animals by decreased selenium-dependent glutathione peroxidase (Se-GSH-Px) activity in all of these tissues. Administration of selenium, as a single intraperitoneal injection of 200 micrograms of selenium (as Na2SeO3)/kg body weight completely reversed the effects of selenium deficiency on thyroid-hormone metabolism and partly restored the activity of Se-GSH-Px. Selenium administration at 10 micrograms/kg body weight had no significant effect on thyroid-hormone metabolism or on Se-GSH-Px activity in any of the tissues studied. The characteristic changes in plasma thyroid-hormone levels that occurred in selenium deficiency appeared not to be due to non-specific stress factors, since food restriction to 75% of normal intake or vitamin E deficiency produced no significant changes in plasma T4 or T3 concentration. These data are consistent with the view that the Type I and Type II iodothyronine deiodinase enzymes are seleno-enzymes or require selenium-containing cofactors for activity.

Animals↗
PubMed1989

Increased indices of lipid peroxidation in stress-susceptible pigs and effects of vitamin E.

When stress-susceptible and stress-resistant pigs consumed diets containing 10 iu vitamin E kg-1, the stress-susceptible pigs had damaged cell membranes. This was indicated by increased plasma activities of creatine kinase and pyruvate kinase. Plasma concentrations of thiobarbituric acid reactive substances and conjugated dienes were also increased suggesting that the membrane damage was caused by free radicals. Susceptibility to free radicals was further demonstrated by an increased tendency for erythrocytes and tissue homogenates from stress-susceptible pigs to peroxidise when incubated with hydrogen peroxide and iron, respectively. Supplementation of the diets with approximately 20 times normal requirements of vitamin E decreased plasma creatine kinase and pyruvate kinase activities, and inhibited the formation of the indices of peroxidation in vivo and in vitro. It is concluded that the stress-susceptible pig has an abnormality in its antioxidant defence mechanisms. However, this abnormality was not due to a deficiency in selenium-dependent glutathione peroxidase, since activities were significantly increased in the longissimus dorsi of stress-susceptible pigs. Although the nature of the antioxidant defect is unclear, it is suggested that stress-susceptible pigs are under a sustained oxidant stress and that a decreased ability to accommodate even a normal free radical load may contribute to the rapid development of the fatal stress response.

Animals↗
PubMed1989

Increased peroxidation of erythrocytes of stress-susceptible pigs: an improved diagnostic test for porcine stress syndrome.

When incubated with solutions of hydrogen peroxide, erythrocytes of stress-susceptible pigs produced more by-products of lipid peroxidation (as measured as thiobarbituric acid-reactive substances [TBARS]) than did erythrocytes from stress-resistant pigs. Using this technique, discrimination between the 2 pig types was absolute at hydrogen peroxide concentrations of 0.9 and 1.5%. This was in contrast to other methods of identifying stress-susceptible pigs, such as osmotically induced erythrocyte lysis and the determination of plasma pyruvate kinase and creatine kinase activities, for which considerable overlap of data was observed between pig types. The increased TBARS production by erythrocytes was further evidence for the existence of an antioxidant abnormality in stress-susceptible pigs. However, because there were no discernible differences in the major blood antioxidant-related values between stress-susceptible and stress-resistant pigs, the nature of the defect remains unclear. The production of TBARS by erythrocytes when incubated with hydrogen peroxide provides an improved method for identifying stress-susceptible pigs.

Animals↗
PubMed1988

The influence of dietary history on the production of free radicals in rat liver microsomes.

Free radicals have been trapped in microsomal fractions from rat livers by the use of alpha-(4-pyridyl-l-oxide)-N-tert-butylnitrone (4-POBN) and detected by ESR spectroscopy. Using this technique we have investigated the effects of low dietary concentrations of vitamin E and selenium (Se) on free radical production. When the microsomal fractions were incubated with Fe, ADP and NADPH significantly greater amounts of radicals were initially trapped when rats were deficient in vitamin E (whether combined with Se deficiency or not) than from Se-deficient animals or Se- and vitamin E-supplemented controls. After prolonged incubation (ca. 30-45 mins) the free radicals trapped from the microsomes from the Se-deficient animals rose to amounts comparable to those seen in the vitamin E-deficient microsomes. Over the same period of incubation approximately half this quantity of radicals were trapped in liver microsomes from Se- and vitamin E-supplemented rats. The effects of 4-POBN on the levels of peroxidation in the various microsomal fractions were assessed by measuring the thiobarbituric acid reactive substances (TBARS). The presence of 4-POBN significantly reduced the amounts of TBARS formed on incubation and there was a clear distinction between the groups on the basis of the vitamin E status of their diets.

Animals↗
PubMed1988

Copper deficiency and tissue glutathione concentration in the rat.

Copper deficiency in rats increased renal vein and arterial (heart) plasma GSH concentration by approximately 50%. There was no change in plasma GSSG concentration. Renal vein plasma GSSG/GSH ratio was decreased in copper deficiency, which is consistent with previous reports showing a copper-dependent thiol oxidase activity in the renal basement membrane. No change occurred in arterial plasma GSSG/GSH ratio. Hepatic GSH concentrations were also elevated by 50% in copper deficiency, GSSG concentrations were unaffected, but GSSG/GSH ratio was depressed. Renal and cardiac tissue GSH and GSSG were unaffected by copper deficiency. The decreased SOD activity and GSH-Px activity observed in copper deficiency may contribute to increased hepatic and plasma GSH concentrations.

Animals↗
PubMed1988

Plasma pyruvate kinase activity vs creatine kinase activity as an indicator of the porcine stress syndrome.

Plasma pyruvate kinase (PK) and creatine kinase (CK) activities were increased significantly (P less than 0.001 and P less than 0.05, respectively) in homozygote halothane-reacting pigs (nn), compared with those activities in homozygote nonreacting pigs (NN). Pyruvate kinase activity was less variable within groups than was CK activity, allowing more effective discrimination between nn and NN geno-types. The PK and CK activities in plasma increase with age in halothane-reacting pigs and the nonreacting pigs. Enzyme activities in heterozygote (Nn) nonreacting pigs did not differ significantly (P greater than 0.05) from enzyme activities of homozygote (NN) nonreacting pigs. Although PK was better than CK in identifying stress-susceptible pigs, age-related effects and the failure to identify heterozygotes may restrict the use of plasma PK activity as a diagnostic test for the stress syndrome.

Animals↗
PubMed1987

Inhibition of hepatic deiodination of thyroxine is caused by selenium deficiency in rats.

Selenium (Se) deficiency produced up to a 14-fold decrease in hepatic tri-iodothyronine (T3) production from thyroxine (T4) in vitro. The T3 production rate could not be restored by the addition of a variety of cofactors, nor by the addition of control homogenate. The impairment in hepatic T3 production observed in Se deficiency was reflected in the concentrations of thyroid hormones circulating in plasma, T4 being increased approx. 40% and T3 being decreased by 30%. However, the fall in plasma T3 concentrations was smaller than might be expected in view of the marked decreased in T3 production. Se deficiency had no measurable effect on plasma reverse-tri-iodothyronine concentrations. The data suggest that Se deficiency produces an inhibition of both 5- and 5'-deiodination, consistent with the widely held view that these reactions are catalysed by the same enzyme complex. The mechanism of inhibition appears not be mediated by changes in thiol levels, but a direct role of Se in the activity of the deiodinase complex cannot be excluded.

Animals↗