| Description: |
The pyrrolizidine alkaloid Heliotrine interferes with reporter signals derived from GAL4-based nuclear receptor transactivation assays by a mechanism independent of luciferase enzyme inhibition. Acute hepatitis induced by Heliotrine is accompanied by uncoupling of oxidative phosphorylation in liver mitochondria.
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| Targets: |
ATPase |
| In vitro: |
| Mol Nutr Food Res. 2014 May;58(5):995-1004. | | Structure-activity relationship in the passage of different pyrrolizidine alkaloids through the gastrointestinal barrier: ABCB1 excretes heliotrine and echimidine.[Pubmed: 24375927] | 1,2-Unsaturated pyrrolizidine alkaloids (PA) are found in plants such as Asteraceae and Boraginaceae families. Acute PA poisoning via contaminated food or feed causes severe damage to liver depending on species-specific oral bioavailability. For assessing PA bioavailability, their passage across the intestinal barrier was investigated using Caco-2 cells.
METHODS AND RESULTS:
Differentiated Caco-2 cells were exposed in transport chambers to the PA heliotrine (Hn), echimidine (Em), senecionine (Sc), and senkirkine (Sk). Cell supernatants were analyzed by LC-MS/MS.
PA pass Caco-2 monolayer from the apical into basolateral compartment depending on their chemical structure. Compared to the cyclic diesters Sc and Sk with a passage rate of 47% ± 4 and 40% ± 3, respectively, the transferred amount of the monoester Hn (32% ± 3) and open-chained diester Em (13% ± 2) was substantially lower. This suggested an active transport of Hn and Em. Using Madin-Darby canine kidney II/P-glycoprotein (ABCB1)-overexpressing cells, the active excretion of Hn and Em by ABCB1 from the gastrointestinal epithelium into the gut lumen was shown.
CONCLUSIONS:
PA cross the intestinal barrier structure-dependently. The passage of the noncyclic PA Hn and Em is reduced by an ABCB1-driven efflux into the gastrointestinal lumen resulting in a decreased oral bioavailability. | | Anal Biochem. 2015 Jul 23. | | Utility of an appropriate reporter assay: Heliotrine interferes with GAL4/UAS-driven reporter gene systems.[Pubmed: 26212314] | Reporter gene assays are widely used for the assessment of transcription factor activation following xenobiotic exposure of cells. A critical issue with such assays is the possibility of interference of test compounds with the test system, for example, by direct inhibition of the reporter enzyme.
METHODS AND RESULTS:
Here we show that the pyrrolizidine alkaloid heliotrine interferes with reporter signals derived from GAL4-based nuclear receptor transactivation assays by a mechanism independent of luciferase enzyme inhibition.
CONCLUSIONS:
These data highlight the necessity to conduct proper control experiments in order to avoid perturbation of reporter assays by test chemicals. |
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| In vivo: |
| Biomed Sci. 1991;2(5):460-4. | | Disturbances in oxidative phosphorylation in the liver of rats with heliotrine-induced hepatitis and restoration by phosphatidylcholine and ATP.[Pubmed: 1668644] | Acute hepatitis induced by heliotrine is accompanied by uncoupling of oxidative phosphorylation in liver mitochondria.
METHODS AND RESULTS:
The rate of oxygen uptake during succinate oxidation increased in all metabolic states, while the respiratory control index decreased by 45% because of the greater increase in the respiration rate in state 4 by comparison with that in state 3. Heliotrine poisoning also halved the rate of oxygen uptake in rat liver homogenates in the presence of ascorbate and tetramethylene-p-phenylenediamine. This is indicative of a lowering of cytochrome oxidase activity and of energy metabolism disturbances in rat liver. Preparations of cotton phosphatidylcholine (PC), both purified and as ATP-containing complexes (PC+ATP), as well as ATP alone, reduced the metabolic disorders in liver mitochondria of rats with acute heliotrine-induced hepatitis.
CONCLUSIONS:
The therapeutic effect of these preparations consisted in the restoration of oxidative phosphorylation coupling and of the cytochrome oxidase activity.
The effect of PC+ATP was much greater than either PC or ATP alone. In contrast, the commercial preparation, Essential, had no beneficial effect. |
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