Metabolism of pyrrolizidine alkaloids in the ovine rumen. I. Formation of 7-α-hydroxy-1-α-methyl-8-α pyrrolizidine from heliotrine and lasiocarpine

1970 ◽  
Vol 21 (3) ◽  
pp. 493 ◽  
Author(s):  
GW Lanigan ◽  
LW Smith
Keyword(s):  
Particulate Matter ◽  
Vitamin B12 ◽  
Pyrrolizidine Alkaloids ◽  
Rumen Fluid ◽  
Pyrrolizidine Alkaloid ◽  
Specific Requirement ◽  
Heliotropium Europaeum ◽  
Alkaloid Metabolism ◽  
Stimulation Of

In vitro studies have demonstrated that the rate of metabolism of pyrrolizidine alkaloids in sheep's rumen fluid varies greatly. Fluids from sheep at pasture display much higher activity than do those from chaff-fed animals. Addition of dried Heliotropium europaeum to a chaff ration leads to a marked increase in the in vitro rate of alkaloid degradation by the rumen fluid but activity rapidly declines again when the H. europaeum is withdrawn. Thus a major factor limiting multiplication in the rumen of bacteria responsible for alkaloid breakdown appears to be lack of their specific substrates. N-oxides of pyrrolizidine alkaloids are rapidly reduced to tertiary bases in rumen fluid, even in samples from sheep not previously exposed to these substrates. The stimulation of the alkaloid-metabolizing system by vitamin B12 also varies greatly, both in whole rumen fluid and in fluids with activity reduced by removal of coarsely particulate matter. It is concluded that the B12 effect is not related to a specific requirement of the alkaloid-utilizing bacteria but to stimulation of other species which produce a metabolite essential for pyrrolizidine alkaloid metabolism.

Metabolism of pyrrolizidine alkaloids in the ovine rumen. IV. Effects of chloral hydrate and halogenated methanes on rumen methanogenesis and alkaloid metabolism in fistulated sheep

1972 ◽  
Vol 23 (6) ◽  
pp. 1085 ◽  
Author(s):  
GW Lanigan
Keyword(s):  
Carbon Tetrachloride ◽  
Pyrrolizidine Alkaloids ◽  
Chloral Hydrate ◽  
Rumen Fluid ◽  
Protective Measure ◽  
Methane Formation ◽  
Heliotropium Europaeum ◽  
Alkaloid Metabolism ◽  
Halogenated Methanes

Five halogenated methane analogues (bromoform, chloroform, iodoform, carbon tetrabromide, and carbon tetrachloride) have been shown to inhibit methane formation in the sheep's rumen as well as in rumen fluid in vitvo. On a molar basis the methane analogues were 100-200 times as effective as chloral hydrate in vitro, but in the rumen this difference was reduced by a factor of 10 with four of the compounds and to parity with chloral hydrate in the case of carbon tetrachloride. When rumen methanogenesis was inhibited by administration of chloral hydrate, bromoform, or iodoform, the time taken for metabolism of 2 g of Heliotropium europaeum alkaloids was reduced to 25-40% of that taken in animals not so treated. These results support the conclusion that inhibition of methanogenesis may be a useful protective measure for sheep ingesting plants which contain hepatotoxic pyrrolizidine alkaloids.

Metabolism of pyrrolizidine alkaloids in the ovine rumen. II. Some factors affecting rate of alkaloid breakdown by rumen fluid in vitro

1970 ◽  
Vol 21 (4) ◽  
pp. 633 ◽  
Author(s):  
GW Lanigan
Keyword(s):  
Pyrrolizidine Alkaloids ◽  
Rumen Fluid ◽  
Metabolic Product ◽  
Factors Affecting ◽  
Methyl Group ◽  
Heliotropium Europaeum ◽  
Methylene Group

When the pyrrolizidine alkaloids heliotrine and lasiocarpine were incubated in vitro with sheep's rumen contents, a common metabolic product was formed. This compound was also found as an end-product of metabolism in the rumen contents of sheep fed on a ration containing the plant Heliotropium europaeum. Previously described rumen metabolites of the Heliotropium alkaloids were 1-methylenepyrrolizidine derivatives, e.g. l-goreensine. The newly found product represents a further stage of reduction of l-goreensine in which the 1-methylene group has been replaced by a 1-methyl group. This compound has been identified as 7�-hydroxyla- methyl-8�-pyrrolizidine, a previously unknown pyrrolizidine derivative.

scholarly journals Hepatotoxicity of Pyrrolizidine Alkaloid Compound Intermedine: Comparison with Other Pyrrolizidine Alkaloids and Its Toxicological Mechanism

Toxins ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 849
Author(s):  
Ziqi Wang ◽  
Haolei Han ◽  
Chen Wang ◽  
Qinqin Zheng ◽  
Hongping Chen ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Pyrrolizidine Alkaloids ◽  
Pyrrolizidine Alkaloid ◽  
Herbal Medicines ◽  
Cell Counting ◽  
Systematic Evaluation ◽  
Sinusoidal Obstruction Syndrome ◽  
Dependent Manner ◽  
Primary Mouse

Pyrrolizidine alkaloids (PAs) are common secondary plant compounds with hepatotoxicity. The consumption of herbal medicines and herbal teas containing PAs is one of the main causes of hepatic sinusoidal obstruction syndrome (HSOS), a potentially life-threatening condition. The present study aimed to reveal the mechanism underlying the cytotoxicity of intermedine (Im), the main PA in Comfrey. We evaluated the toxicity of the retronecine-type PAs with different structures to cell lines derived from mammalian tissues, including primary mouse hepatocytes, human hepatocytes (HepD), mouse hepatoma-22 (H22) and human hepatocellular carcinoma (HepG2) cells. The cytotoxicity of Im to hepatocyte was evaluated by using cell counting kit-8 assay, colony formation experiment, wound healing assay and dead/live fluorescence imaging. In vitro characterization showed that these PAs were cytotoxic and induced cell apoptosis in a dose-dependent manner. We also demonstrated that Im induced cell apoptosis by generating excessive reactive oxygen species (ROS), changing the mitochondrial membrane potential and releasing cytochrome c (Cyt c) before activating the caspase-3 pathway. Importantly, we directly observed the destruction of the cell mitochondrial structure after Im treatment through transmission electron microscopy (TEM). This study provided the first direct evidence of Im inducing hepatotoxicity through mitochondria-mediated apoptosis. These results supplemented the basic toxicity data of PAs and facilitated the comprehensive and systematic evaluation of the toxicity caused by PA compounds.

scholarly journals Regulatory Perspectives of Pyrrolizidine Alkaloid Contamination in Herbal Medicinal Products

Planta Medica ◽  
2021 ◽  
Author(s):  
Jacqueline Wiesner
Keyword(s):  
Animal Studies ◽  
Pyrrolizidine Alkaloids ◽  
Pyrrolizidine Alkaloid ◽  
European Medicines Agency ◽  
Medicinal Products ◽  
Herbal Medicinal Products ◽  
Herbal Medicinal ◽  
National Competent Authorities

AbstractThe toxicity of plants containing certain pyrrolizidine alkaloids has long been recognized in grazing animals and humans. Genotoxicity and carcinogenicity data from in vitro and in vivo (animal) studies were published over the last few decades for some of the 1,2-unsaturated pyrrolizidine alkaloids, leading to regulatory action on herbal medicinal products with pyrrolizidine alkaloid-containing plants more than 30 years ago. In recent years, it has become evident that in addition to herbal medicinal products containing pyrrolizidine alkaloid-containing plants, these products may also contain pyrrolizidine alkaloids without actually including pyrrolizidine alkaloid-containing plants. This is explained by contamination by accessory herbs (weeds). The national competent authorities of the European member states and the European Medicines Agency, in this case, the Committee on Herbal Medicinal Products, reacted to these findings by setting limits for all herbal medicinal products. This review article will briefly discuss the data leading to the establishment of thresholds and the regulatory developments and consequences, as well as the current discussions and research in this area.

scholarly journals Novel Insights into Pyrrolizidine Alkaloid Toxicity and Implications for Risk Assessment: Occurrence, Genotoxicity, Toxicokinetics, Risk Assessment–A Workshop Report

Planta Medica ◽  
2021 ◽  
Author(s):  
Dieter Schrenk ◽  
Jörg Fahrer ◽  
Ashley Allemang ◽  
Peter Fu ◽  
Ge Lin ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Pyrrolizidine Alkaloids ◽  
Liver Toxicity ◽  
Pyrrolizidine Alkaloid ◽  
International Workshop ◽  
Response Analysis ◽  
Medicinal Products ◽  
Widespread Occurrence ◽  
Animal Data

AbstractThis paper reports on the major contributions and results of the 2nd International Workshop of Pyrrolizidine Alkaloids held in September 2020 in Kaiserslautern, Germany. Pyrrolizidine alkaloids are among the most relevant plant toxins contaminating food, feed, and medicinal products of plant origin. Hundreds of PA congeners with widespread occurrence are known, and thousands of plants are assumed to contain PAs. Due to certain PAsʼ pronounced liver toxicity and carcinogenicity, their occurrence in food, feed, and phytomedicines has raised serious human health concerns. This is particularly true for herbal teas, certain food supplements, honey, and certain phytomedicinal drugs. Due to the limited availability of animal data, broader use of in vitro data appears warranted to improve the risk assessment of a large number of relevant, 1,2-unsaturated PAs. This is true, for example, for the derivation of both toxicokinetic and toxicodynamic data. These efforts aim to understand better the modes of action, uptake, metabolism, elimination, toxicity, and genotoxicity of PAs to enable a detailed dose-response analysis and ultimately quantify differing toxic potencies between relevant PAs. Accordingly, risk-limiting measures comprising production, marketing, and regulation of food, feed, and medicinal products are discussed.

COMPARITIVE TOXICITY AND METABOLISM OF PYRROLIZIDINE ALKALOIDS IN RUMINANTS AND NONRUMINANT HERBIVORES

1984 ◽  
Vol 64 (5) ◽  
pp. 201-202 ◽  
Author(s):  
P. R. CHEEKE
Keyword(s):  
Body Weight ◽  
Key Words ◽  
Guinea Pigs ◽  
Pyrrolizidine Alkaloids ◽  
Rumen Fluid ◽  
Pyrrolizidine Alkaloid ◽  
Lethal Dose ◽  
Metabolizing Enzymes ◽  
Sheep Rumen ◽  
Tansy Ragwort

The toxicity of tansy ragwort (Sencio jacobaea) to several ruminant and nonruminant species was tested. Cattle and horses were susceptible (lethal dose of tansy ragwort (TR) was 4–8% of body weight) whereas sheep and goats were resistant (lethal dose of TR was 200–300% of body weight). Other nonruminant herbivoires (rabbits, gerbils, guinea pigs, hamsters) were resistant to TR. Incubation of TR in sheep rumen fluid did not alter its toxicity to rats. No 1-methylene pyrrolizidine alkaloid (PA) derivatives were detected in TR incubated in sheep rumen fluid. The activities of PA-metabolizing enzymes in sheep liver were not influenced by dietary TR. Key words: Pyrrolizidine alkaloids, ruminants, nonruminant herbivores

Metabolism of pyrrolizidine alkaloids in the ovine rumen. III. The competitive relationship between Heliotrine metabolism and methanogenesis in the rumen fluid in vitro

1971 ◽  
Vol 22 (1) ◽  
pp. 123 ◽  
Author(s):  
GW Lanigan
Keyword(s):  
Rumen Fluid ◽  
Methanogenic Bacteria ◽  
Hydrogen Gas ◽  
Maximal Rate ◽  
Carbon Dioxide Atmosphere ◽  
Effective Prophylaxis ◽  
Heliotropium Europaeum ◽  
Sheep Rumen

Inclusion of up to 80% hydrogen in the gas phase markedly stimulated the in vitro metabolism of heliotrine in sheep rumen fluid. The maximal rate of heliotrine breakdown under these conditions was twice that obtained when cyanocobalamin was added and 10 times the rate in unsupplemented rumen fluid. A maximal rate of heliotrine metabolism equal to that in the presence of 80% hydrogen gas could be obtained with a pure carbon dioxide atmosphere if certain inhibitors of methanogenic bacteria were added to the rumen fluid. It is concluded that the heliotrine-metabolizing bacteria are normally at a disadvantage in competition with the methanogenic bacteria for metabolic hydrogen, and that inhibition of the latter organisms in vivo could provide a basis for development of effective prophylaxis in sheep at risk with Heliotropium europaeum in the field.

Early Platelet-Collagen Interactions in Whole Blood and Their Modifications by Aspirin and Dipyridamole Evaluated by a New Method (Basic Wave)

1985 ◽  
Vol 54 (04) ◽  
pp. 799-803 ◽  
Author(s):  
José Luís Pérez-Requejo ◽  
Justo Aznar ◽  
M Teresa Santos ◽  
Juana Vallés
Keyword(s):  
Whole Blood ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
White Blood Cells ◽  
Reversible Aggregation ◽  
Inhibitory Compounds ◽  
Rapid Generation ◽  
Stimulation Of ◽  
Collagen Stimulation

SummaryIt is shown that the supernatant of unstirred whole blood at 37° C, stimulated by 1 μg/ml of collagen for 10 sec, produces a rapid generation of pro and antiaggregatory compounds with a final proaggregatory activity which can be detected for more than 60 min on a platelet rich plasma (PRP) by turbidometric aggregometry. A reversible aggregation wave that we have called BASIC wave (for Blood Aggregation Stimulatory and Inhibitory Compounds) is recorded. The collagen stimulation of unstirred PRP produces a similar but smaller BASIC wave. BASIC’s intensity increases if erythrocytes are added to PRP but decreases if white blood cells are added instead. Aspirin abolishes “ex vivo” the ability of whole blood and PRP to generate BASIC waves and dipyridamole “in vitro” significantly reduces BASIC’s intensity in whole blood in every tested sample, but shows little effect in PRP.

DER EINFLUSS VON RESERPIN AUF DIE ANTITHYREOIDALE WIRKUNG VON KALIUMPERCHLORAT

1962 ◽  
Vol 39 (3) ◽  
pp. 423-430
Author(s):  
H. L. Krüskemper ◽  
F. J. Kessler ◽  
E. Steinkrüger
Keyword(s):  
Thyroid Gland ◽  
Male Rats ◽  
Normal Male ◽  
Tissue Respiration ◽  
List Type ◽  
Morphological Alterations ◽  
Hormone Synthesis ◽  
Stimulation Of

ABSTRACT 1. Reserpine does not inhibit the tissue respiration of liver in normal male rats (in vitro). 2. The decrease of tissue respiration of the liver with simultaneous morphological stimulation of the thyroid gland after long administration of reserpine is due to a minute inhibition of the hormone synthesis in the thyroid gland. 3. The morphological alterations of the thyroid in experimental hypothyroidism due to perchlorate can not be prevented with reserpine.

EFFECT OF ACTINOMYCIN D ON TSH-INDUCED STIMULATION OF THYROIDAL PROTEIN SYNTHESIS IN THE RAT

1974 ◽  
Vol 77 (1) ◽  
pp. 64-70 ◽  
Author(s):  
Gustav Wägar
Keyword(s):  
Protein Synthesis ◽  
Actinomycin D ◽  
The Other ◽  
Leucine Incorporation ◽  
Short Term ◽  
Other Hand ◽  
Thyroid Glands ◽  
Translational Level ◽  
Stimulation Of

ABSTRACT Whether the short-term regulation of thyroidal protein synthesis by TSH occurs at the transcriptional or the translational level was tested by measuring the effect of actinomycin D (act D) on the TSH-induced stimulation of L-14C-leucine incorporation into the thyroidal proteins of rats. TSH was injected 6 h before the rats were killed. The thyroid glands were then removed and incubated in vitro in the presence of L-14C-leucine for 2 h. The pronounced stimulation of leucine incorporation in the TSH-treated animals was depressed as compared with controls but still significant even when the animals had been pre-treated with 100 μg act D 24 and 7 h before sacrifice. On the other hand, act D strongly decreased incorporation of 3H-uridine into RNA. Short-term regulation of thyroidal protein synthesis by TSH appears to be partly but not wholly dependent on neosynthesis of RNA. Hence regulation may partly occur at the translation level of protein synthesis.

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