Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.1.1.32 (phosphoenolpyruvate carboxykinase)
 4,204 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hypothesis tested in this experiment is that effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) show identical dose-responses after subchronic as after acute exposure when the dose is corrected for toxicokinetics. Groups of male Sprague-Dawley (S-D) rats were administered orally a total dose of 0, 0.2, 2.3, 11.5, 35, 70 or 115 micrograms/kg of TCDD over a period of 10 weeks at 4 ml/kg of vehicle. Body weight was recorded weekly. One week after the last dose of TCDD one half of the rats was killed and tryptophan 2,3-dioxygenase (TdO), 7-ethoxyresorufin-O-deethylase (EROD) and phosphoenolpyruvate carboxykinase (PEPCK) activities were measured in livers, whereas tryptophan and total T4 (TT4) were determined in serum. The results show that the dose-response for decreased TdO and PEPCK activity and elevated serum tryptophan levels are similar if not the same as the dose-response for subchronic retardation of body weight increase. They also demonstrate that the dose-responses for the induction of EROD activity and the reduction of serum TT4 occurred at much lower doses than those for decreased TdO and PEPCK activities or elevated tryptophan levels and mortality. After a 6-week recovery period, PEPCK and TdO activities in liver as well as tryptophan in serum returned to near control values, whereas EROD activity and serum TT4 still displayed a dose-dependent induction and reduction, respectively, albeit both shifted to the right in accordance with toxicokinetics. These data support the notion that subchronic dose-responses of TCDD are similar to acute dose-responses when corrected for toxicokinetics and that at least some TCDD-induced effects are reversible also in accordance with toxicokinetics.
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PMID:Subchronic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and their reversibility in male Sprague-Dawley rats. 771 79

The aim of this study was to examine the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin, (TCDD) in a rat strain other than the Sprague-Dawley (S-D) rat, for which most of our data have been generated thus far. Doses for the biochemical study were selected based on an acute range-finding study, which indicated that Long-Evans (L-E) rats are somewhat less susceptible to TCDD toxicity than are S-D rats. Male L-E rats were dosed orally with 10, 20, 45, 67, 100 and 150 micrograms/kg TCDD. Body weight and feed intake were dose-dependently decreased prior to killing of the animals. Eight days after dosing, animals were killed and tryptophan, total T4 (TT4) and total T3 (TT3) levels were determined in serum, whereas the activities of ethoxy-resorufin-O-deethylase (EROD), phosphoenolpyruvate carboxykinase (PEPCK), gamma-glutamyl transpeptidase (gamma-GT) and tryptophan 2,3-dioxygenase (TdO) were measured in liver. EROD activity was fully induced at all doses studied, indicating that as in S-D rats, Ah-receptor-mediated effects do not seem to play any major role in the acute toxicity of TCDD in this rat strain either. Hepatic PEPCK activity was dose-dependently decreased in a similar dose range as in S-D rats, indicating inhibition of gluconeogenesis. Feed intake was dose-dependently decreased as a result of a dose-dependent elevation in serum tryptophan levels, which in turn were related to reduced liver TdO activity. Hepatic gamma-GT activity was also dose-dependently reduced.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Relationship between acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and disturbance of intermediary metabolism in the Long-Evans rat. 771 64

The aim of this study was to examine short- and long-term biochemical effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in female Long-Evans (L-E) rats. In the short-term study, female rats were dosed orally with 5.3, 12, 18 and 60 micrograms TCDD/kg and sacrificed 4 days after dosing. In the long-term study, rats were dosed with 27, 40 and 60 micrograms TCDD/kg and sacrificed 90 days after dosing. Four days after dosing, ethoxyresorufin O-deethylase (EROD) activity was fully induced at all doses studied, hepatic phosphoenolpyruvate carboxykinase (PEPCK) and gamma-glutamyl transpeptidase (gamma-GT) activities were dose-dependently reduced, whereas hepatic tryptophan 2,3-dioxygenase (TdO) activity was stimulated at low doses but decreased at high doses. Serum total T4 (TT4) levels were dose-dependently decreased, whereas serum total T3 (TT3) and tryptophan levels were unaffected. The short-term effects of TCDD examined in this study indicate only small differences in the response of female L-E rats to TCDD as compared to males. Ninety days after dosing, liver EROD activity revealed considerable reversibility although it was still elevated compared to controls. Hepatic PEPCK activity at this time point was no more different from controls. In contrast to 4 days after dosing, serum TT3, TT4 and hepatic gamma-GT activity were dose-dependently elevated at the 90-day time point. These findings have significant implications for the interpretations of subchronic and chronic effects of TCDD on thyroid homeostasis and on the formation of preneoplastic liver foci.
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PMID:Short- and long-term biochemical effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Long-Evans rats. 786 29

Groups of 20 male and 20 female rats were given five different oral doses of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) or one dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) divided into four daily loading doses and six biweekly maintenance doses. The dosing period was 13 weeks, after which half of the rats were necropsied and the rest assigned to an off-dose period of another 13 weeks. At the end of the dosing period, liver ethoxyresorufin O-deethylase (EROD) activity was dose-dependently increased starting at the lowest dose (7- to 10-fold) with maximum induction (50- to 100-fold) at the middle or second highest dose. There was a slight reversibility of this effect in HpCDD-treated rats, particularly at lower doses, and a pronounced reversibility in TCDD-dosed rats, both in accordance with respective toxicokinetics. The activity of phosphoenolpyruvate carboxykinase in liver was dose-dependently decreased (up to 60%) at the two or three highest doses of HpCDD and also in the TCDD dosage group. Liver tryptophan 2,3-dioxygenase activity was decreased at the two highest doses of HpCDD (up to 41%), particularly in females. Serum tryptophan concentrations were elevated in rats found moribund due to wasting. There was a dose-dependent decrease in serum glucose concentrations (up to 30%) at the end of the dosing period. Serum thyroxin (T4) concentrations showed a dose-dependent decrease (78% at the highest dose) beginning in the middle dose for HpCDD and in the TCDD dosage group. Serum triiodothyronine (T3) concentrations were only slightly affected, except that they were somewhat decreased in moribund animals. The results demonstrate that similar biochemical changes occur in rats after single as after multiple dosing with HpCDD and TCDD. Based on these endpoints, the relative potency of HpCDD after subchronic exposure is in agreement with the international toxic equivalency factor (I-TEF) of 0.01 and, more specifically, with a TEF of 0.007 based on LD50 values in the same strain of rats.
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PMID:Subchronic/chronic toxicity of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) in rats. Part II. Biochemical effects. 934 89

Groups of 20 male and 20 female rats were given five different oral doses of a mixture of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1, 2,3,7,8-pentaCDD, (PCDD) 1,2,3,4,7,8-hexaCDD (HxCDD), and 1,2,3,4,6, 7,8-heptaCDD (HpCDD) divided into four daily loading doses and six biweekly maintenance doses. PCDD and HxCDD were used as positive controls. The dosing period was 13 weeks, after which half of the rats were necropsied and the rest provided with an off-dose period of another 13 weeks. Liver ethoxyresorufin O-deethylase (EROD) activity was dose-dependently increased in rats dosed with the mixture starting at the lowest dose (13- to 16-fold increase), with the effect reaching maximum at the middle dosage (74- to 112-fold increase), as well as in the positive control groups. There was some indication of reversibility at the lower doses and in positive controls during the off-dose period. The activity of phosphoenolpyruvate carboxykinase (PEPCK) in liver was dose-dependently decreased (maximally by 51%). This effect was more distinct in males than in females. Liver tryptophan 2,3-dioxygenase (TdO) activity decreased maximally by 53% at the two highest doses. This effect was more distinct in females than in males. Serum tryptophan concentrations were increased in rats moribund due to wasting. Some reversibility was apparent by the end of the off-dose period regarding all three biochemical markers of CDD toxicity. Serum glucose concentrations were decreased at the three highest doses of the mixture and in positive controls, maximally by 30%, with some reversibility during the off-dose period. There was a dose-dependent decrease of serum thyroxine (T4) concentrations in rats given the mixture and in the PCDD and HxCDD dosage groups (maximally by 69%), with some reversibility in males during the off-dose period. Serum triiodothyronine (T3) levels were not much affected, except that they tended to be decreased in rats moribund with hemorrhage or anemia. The results demonstrate that comparable biochemical changes occur after multiple as after single dosing with CDDs and that TEFs derived from acute studies can be used to predict the toxicity of mixtures of CDDs regardless whether they are administered as single compounds or as a mixture. This study supports the validity of the toxic equivalency factor (TEF) method and the notion of additive toxicity for CDDs as currently used in the risk assessment of these compounds.
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PMID:Subchronic/chronic toxicity of a mixture of four chlorinated dibenzo-p-dioxins in rats. II. Biochemical effects. 970 88