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PubMed2005

Metabolic activation of the tumorigenic pyrrolizidine alkaloid, retrorsine, leading to DNA adduct formation in vivo.

Pyrrolizidine alkaloids are naturally occurring genotoxic chemicals produced by a large number of plants. The high toxicity of many pyrrolizidine alkaloids has caused considerable loss of free-ranging livestock due to liver and pulmonary lesions. Chronic exposure of toxic pyrrolizidine alkaloids to laboratory animals induces cancer. This investigation studies the metabolic activation of retrorsine, a representative naturally occurring tumorigenic pyrrolizidine alkaloid, and shows that a genotoxic mechanism is correlated to the tumorigenicity of retrorsine. Metabolism of retrorsine by liver microsomes of F344 female rats produced two metabolites, 6, 7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP), at a rate of 4.8 +/- 0.1 nmol/mg/min, and retrorsine-N-oxide, at a rate of 17.6 +/- 0.5 nmol/mg/min. Metabolism was enhanced 1.7-fold by using liver microsomes prepared from dexamethasone-treated rats. DHP formation was inhibited 77% and retrorsine N-oxide formation was inhibited 29% by troleandomycin, a P450 3A enzyme inhibitor. Metabolism of retrorsine with lung, kidney, and spleen microsomes from dexamethasone-treated rats also generated DHP and the N-oxide derivative. When rat liver microsomal metabolism of retrorsine occurred in the presence of calf thymus DNA, a set of DHP-derived DNA adducts was formed; these adducts were detected and quantified by using a previously developed 32P-postlabeling/HPLC method. These same DNA adducts were also found in liver DNA of rats gavaged with retrorsine. Since DHP-derived DNA adducts are suggested to be potential biomarkers of riddelliine-induced tumorigenicity, our results indicate that (i) similar to the metabolic activation of riddelliine, the mechanism of retrorsine-induced carcinogenicity in rats is also through a genotoxic mechanism involving DHP; and (ii) the set of DHP-derived DNA adducts found in liver DNA of rats gavaged with retrorsine or riddelliine can serve as biomarkers for the tumorigenicity induced by retronecine-type pyrrolizidine alkaloids.

Animals↗
PubMed2004

[A study on anti-inflammatory and analgesic effects of alkaloids of Toddalia asiatica].

OBJECTIVE: To study the pharmacological activities and toxicity of the crude alkaloids of Toddalia asiatica and to provide pharmacological data for the further development of this herbal medicine. METHODS: We observed the anti-inflammatory effects of the crude alkaloids of Toddalia asiatica, using xylol and agra to induce the turgidness and sodium carboxymethyl cellulose (CMC-Na) to induce leucocyte strolling in the rats. The analgesic effects were observed by body-distortion methods. The effects of alkaloids of Toddalia asiatica on hepatic function were observed by testing the contents of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum and calculating the liver index. The LD 50 and 95% creditability were calculated with developed Karber Method. RESULTS: The administration of alkaloids of Toddalia asiatica had the function of inhibiting the auricle swelling caused by xylol and joint swelling caused by agar and leucocyte migration caused by CMC-Na, decreasing the body-distortion of the rats. After two weeks administration, the contents of ALT and AST showed that there was no obvious difference between administered group and control group. The LD50 of the crude alkaloids of Toddalia asiatica was 1.622 g/kg and the 95% creditability was 1.29-2.03 g/kg. CONCLUSION: Toddalia asiatica has anti-inflammatory and analgesic effects, and there is no injury to the liver after long-term administration in rats.

Alanine Transaminase↗
PubMed1998

Cytotoxicities of alkaloids from processed and unprocessed seeds of Strychnos nux-vomica.

AIM: To examine the cytotoxicities of 6 crude Strychnos alkaloid fractions from the seeds of Strychnos nux-vomica unprocessed or processed with various traditional processing methods and 13 pure Strychnos alkaloids from the fractions. METHODS: Using cell culture, their inhibitory effects on Vero cell growth-inhibition assay, and host cell DNA synthesis by [3H]thymidine ([3H]TdR) uptake assay. RESULTS: The IC50 of processed seeds were 155% and 212% of unprocessed ones in cell growth-inhibition assay and in [3H]TdR uptake assay, respectively. The IC50 of 13 compounds were 0.45-0.80 mmol.L-1 and 0.50-12 mmol.L-1, respectively. The processing method with sand bath exhibited a wide safety margin compared with other traditional processing methods or no processing. The isomers of Strychnos alkaloids and their N-oxides showed much lower cytotoxicities among these alkaloids. Isobrucine N-oxide showed the lowest cytotoxicity. The contents of isomers and N-oxides of Strychnos alkaloids were the highest in the sand processing. CONCLUSION: Processing of nux vomica plays a critical role in its toxicity.

Alkaloids↗
PubMed1976

Spectrophotometric analysis of alkaloids with picrolonic acid.

The spectroscopic characteristics of the interaction of alkaloids with picrolonic acid were studied. In solvents of low and intermediate polarity, the presence of alkaloids caused a red shift of the 322 nm band of nonionized picrolonic acid to 355 nm, corresponding to the anionic resonance band. There was also a considerable increase in absorptivity, which was dependent on both the basicity (pKa) and molar concentration of the alkaloid present. Arylamines, aromatic N-heterocycles, and alkaloids lacking an aliphatic amine moiety did not show observable shifts. The interaction was developed into a spectrophotometric assay for the following alkaloids in pharmaceutical preparations: atropine, ephedrine, codeine, emetine, quinine, and strychnine. The method is sensitive to 2 mug alkaloid/ml, with an accuracy of not equal to 1.5% and a standard deviation of not equal to 1.05 - 1.31%.

Alkaloids↗
PubMed1976

[Mechanism of action of some quinoline alkaloids on respiratory chain of mitochondria].

The mechanism of action of some quinoline alkaloids and their derivatives on respiratory chain of rat liver and Candida lipolytica yeast mitochondria was studied. The alkaloids were shown to inhibit electron transfer in the respiratory chain. The site of their action is localized between b and c cytochromes. Besides their ability to inhibit electron transfer in the respiratory chain, alkaloids are shown to be specific inhibitors of "exogenous" NADH-dehydrogenase of C. lipolytica yeast mitochondria. In addition to their inhibiting properties alkaloids can stimulate ATPase activity of mitochondria. O-alkylation of pseudane-IX permits to differentiate the inhibiting and uncoupling properties of this alkaloid.

Adenosine Triphosphatases↗
PubMed2003

[Inhibition of liver mitochondrial monoamine oxidase activity by alkaloids isolated from Chelidonium and Macleaya and by their derivative drugs].

It has been shown that the major alkaloids from plants Chelidonium majus L. and Macleaya (Bocconia) cordata and microcarpa, namely, berberine, sanguinarine, chelidonine, and drugs "Ukrain" (thiophosphoric acid derivative of a sum of the alkaloids isolated from Ch. majus L.) and "Sanguirythrine" (a mixture of the alkaloids sanguinarine and chelerythrine, w/w 3:7, isolated from Macleaya), are irreversible inhibitors of oxidative deamination reaction of serotonin and tyramine as substrates, catalyzed by rat liver mitochondrial monoamine oxidase (MAO). At the same time these substances do not influence the oxidative deamination reaction of benzylamine as substrate (in concentration 1 mM or less). The substrate specificity of this inhibition manifests that mainly the oxidative deamination reactions catalyzed by MAO form A are inhibited by the agents studied. Among the examined agents, alkaloid chelidonine and drug "Ukrain" are the strongest inhibitors of the reaction. Alkaloids berberine and sanguinarine and drug "Sanguirythrine" exhibit a weaker action. Judging from the data obtained, sanguinarine and chelerythrine appear to exert similar inhibitory effects in this reaction, since sanguinarine and "Sanguirythrine" have similar values of bimolecular rate constants of their interaction with mitochondrial MAO. As it is well known, the MAO inhibitors appear to be, as a rule, pronounced antidepressants. The combination of malignotoxicity and antidepressive activity in drug "Ukrain" seems to be favourable for its clinical applications.

Alkaloids↗
PubMed2005

[Total alkaloid of Macleaya cordata: in vitro cytotoxic effect on Hep3B cells and in vivo antitumor effect in mice].

OBJECTIVE: To observe the cytotoxic effects in vitro and antitumor effects in vivo of total alkaloid of Macleaya cordata. METHODS: MTT assay was used to assess the proliferation of Hep3B and H22 cells in vitro treated with the alkloid, and the inhibitory effects of the alkaloid on H22 and S180 tumors were observed in mice with subcutaneous inoculation of the tumor cells. RESULTS: The total alkaloid significantly inhibited the proliferation of human Hep3B cells and murine H22 cells in a dose-dependent in vitro. IC(50) of the alkloid in 3 repeated experiments was 3.04, 3.98 and 2.98 mug/ml respectively in Hep3B cells, and was 2.89, 2.21 and 2.34 mug/ml in H22 cells. In the tumor-bearing mice, the alkaloid inhibited the development of H22 tumor and prolonged the survival of S180 tumor-bearing mice. At the daily dose of 1, 2, and 4 mg/kg.b.w (i.p.) and 4 mg/kg.b.w. (i.g.) for 10 days, the inhibition rates of the alkaloid on H22 tumor in 3 repeated experiments were 18.6%, 35.1%, 44.9% and 7.9% respectively, and the rates of survival prolongation of the tumor-bearing mice were 24.8%, 48.9%, and 52.7%, respectively. CONCLUSION: The alkloid possesses antitumor effects both in vitro and in vivo.

Alkaloids↗
PubMed2004

[Isolation and identification of alkaloids from Armeniaca mume Sieb].

OBJECTIVE: To study the alkaloids from Armeniaca mume Sieb. METHODS: The alkaloids were extracted with chloroform from 80% alcoholic extract and concentrated. Then they were transferred into aqueous solution and absorbed by macroporous cation exchange resin. The concentrated total eluent was extracted with chloroform. The alkaloids were purified by recrystallization with petroleum ether and sublimation. Then they were determined by Fourier Transform Infrared spectroscopy, Mass spectrometry and Nuclear magnetic resonance etc methods. RESULT: Two alkaloids were separated and their structures were elucidated as 2,2,6,6-tetramethyl-4-piperidone and tert-butylurea on the basis of spectral evidence. CONCLUSION: They are new alkaloids from A. mume.

Alkaloids↗
PubMed1992

In vitro ruminal metabolism of larkspur alkaloids.

Larkspur (Delphinium sp) poisoning of range cattle is a serious, recurring problem in the western United States. Numerous stratagems have been recommended to ameliorate larkspur intoxication, but none are completely effective. Previous studies in this laboratory indicated bovine ruminal microflora are capable of chemically modifying Delphinium alkaloids. Research reported herein was undertaken to further evaluate whether differences in ovine and bovine rumen metabolism might explain differences in susceptibility to larkspur intoxication and whether existing metabolic activity can be enhanced by sustained exposure to Delphinium alkaloids. Comparison of ovine and bovine rumen metabolism of Delphinium geyeri alkaloids in vitro failed to demonstrate differences in the rate of alkaloid metabolism. Rumen liquor collected sequentially from a fistulated cow dosed with dried Delphinium geyeri did not vary in ability to metabolize larkspur alkaloids.

Alkaloids↗
PubMedDate not supplied

Method for the determination of Aconitum alkaloids in dietary supplements and raw materials by reversed-phase liquid chromatography with ultraviolet detection and confirmation by tandem mass spectrometry: single-laboratory validation.

A study of single-laboratory validation (SLV) of a reversed-phase liquid chromatography (RP-LC) method was conducted for the determination of diester-diterpene Aconitum alkaloids, viz., aconitine, mesaconitine, and hypaconitine, in a variety of dietary supplements, including single- and multiple-ingredient dry powder extracts, pills, capsules, and raw materials. The Aconitum alkaloids in the samples were extracted by diethyl ether in the presence of ammonia. After cleanup with solid-phase extraction to remove the matrix interferences, the alkaloids were determined by RP-LC with UV detection at 235 nm, and the results were confirmed by tandem mass spectrometry. The linear responses for aconitine, mesaconitine, and hypaconitine based on the present LC system ranged from 0.5 to 200 microg/mL. Relative standard deviations of 2.0 to 6.9% were obtained from duplicate analysis of 6 test materials of different matrixes for the 3 Aconitum alkaloids performed by 2 analysts on 5 different days. The recoveries determined for supplements and raw materials spiked with 3 Aconitum alkaloids at levels of 2.5-10 microg/g were in the range of 86-99%. In view of the attainment of satisfactory results for accuracy, precision, and recovery in the SLV study, it is recommended that the method validation process proceed to a collaborative study.

Aconitum↗
PubMed1991

Bioconversions of ergot alkaloids.

Ergot alkaloids are very important pharmaceutical substances with wide medical use. Their bioproduction is usually followed by chemical modification. Bioconversions of ergot alkaloids on an industrial scale have become more important in recent years. The aim of this study is to collect the available data on ergot alkaloid bioconversions and to show their potential applications. The paper deals with conversions of clavines, e.g. biooxidations, glycosylations of the alkaloids, and bioconversions of lysergic acid derivatives. A part of it is aimed at bioconversions of ergot alkaloids in mammalian organisms and obtaining their metabolites by biotransformation. The use of immobilized systems and cofermentation is also discussed.

Animals↗
PubMed1986

Reversal of Vinca alkaloid resistance but not multiple drug resistance in human leukemic cells by verapamil.

We examined the ability of verapamil, a Ca2+ channel blocker, to overcome Vinca alkaloid and multiple drug resistance in our CEM/VLB100 and CEM/DOX human leukemic lymphoblasts. Compared with the parent CCRF-CEM cells, CEM/VLB100 cells are approximately equal to 200- to 800-fold resistant to vinblastine and express cross-resistance to vincristine, doxorubicin, and other "natural product" drugs, as determined by comparing 50% inhibitory concentrations in a 48-h growth inhibition assay. Verapamil (10 microM) decreased the 50% inhibitory concentrations for Vinca alkaloids in CEM/VLB100 cells by approximately equal to 75- to 85-fold but caused only slight (approximately equal to 2- to 5-fold) decreases in 50% inhibitory concentrations for anthracyclines, epipodophyllotoxins, and other tubulin-binding drugs (colchicine and podophyllotoxin). Qualitatively similar results were obtained with doxorubicin-resistant cells, termed CEM/DOX; verapamil caused a 19-fold increase in doxorubicin toxicity but 67- and 3500-fold increases in the toxicities of vinblastine and vincristine, respectively. These results indicate that the effect of verapamil is relatively greater for Vinca alkaloids, with less pronounced effects for the other natural product drugs against which these cells express multiple drug resistance. In flow cytometric studies, individually nontoxic or minimally toxic concentrations of vinblastine plus verapamil caused measurable accumulation in the G2 + M phase as early as 4 h after the drug combination was added to cultures of CEM/VLB100 cells; this finding correlated with a comparable increase in the number of cells in mitosis and measurable decreases in the total number of cells. Since similar effects on cell cycle distribution, percentage of cells in mitosis, and cell number were seen when CEM/VLB100 cells were treated with toxic concentrations of vinblastine alone, we conclude that the primary toxicity of the vinblastine-verapamil combination stems from the alkaloid. Further, the rapid lytic effect of the drug combination was associated with cellular vacuolization. The vacuoles did not stain for lipids, and increases in their number were evident within 2 to 4 h after drug treatment. We suggest that verapamil enhances Vinca alkaloid cytotoxicity by altering "cryptic" cytotoxic targets, possibly related to these vacuoles, through some as yet undefined membrane effect.

Cell Cycle↗
PubMed1987

Specific Vinca alkaloid-binding polypeptides identified in calf brain by photoaffinity labeling.

A radioactive, photoactive Vinca alkaloid, N-(p-azido-[3,5-3H]-benzoyl)-N'-beta-aminoethylvindesine [( 3H]NABV) with pharmacological and biological activities similar to vinblastine was synthesized and used to identify specific Vinca alkaloid macromolecular interactions in calf brain homogenate by photoaffinity labeling. The most prominent photolabeled species were 54.3- and 21.5-kDa polypeptides. The Vinca alkaloid-binding specificity of these polypeptides was confirmed by competitive blocking of specific photolabeling by vinblastine but not by colchicine or daunorubicin. The 54.3- and 21.5-kDa polypeptides exhibited specific half-maximum saturable photolabeling at 2.1 and 0.95 X 10(-7) M [3H]NABV, respectively. Relative vinblastine and NABV association constants (Ka vinblastine/Ka NABV) for the 54.3- and 21.5-kDa polypeptides were estimated to be 0.86 and 1.4, respectively. The 54.3-kDa component was found in both high speed (100,000 X g; 1 h) pellet and supernatant fractions, whereas the 21.5-kDa component was located primarily in the high speed pellet. Photolabeling of both components was maximal after 12-min UV light exposure, linear up to 120 micrograms of homogenate protein and only slightly affected by the nitrene scavenger p-aminobenzoic acid. The 54.3-kDa polypeptides of [3H]NABV-photolabeled calf brain high speed supernatant and detergent-solubilized high speed pellet fractions were identified as tubulin subunits by immunoprecipitation with monoclonal antibodies to alpha- or beta-tubulin subunits. Although the identity and function of the 21.5-kDa polypeptide is not known, this polypeptide may have a role in membrane-related effects of the Vinca alkaloids. These results demonstrate that [3H]NABV is an attractive tool for identifying and characterizing specific high affinity vinblastine cellular polypeptide acceptors which may initiate or mediate known and unknown mechanisms of Vinca alkaloid action.

4-Aminobenzoic Acid↗
PubMed1983

Interactions of ergot alkaloids with anterior pituitary D-2 dopamine receptors.

The interactions of ergot alkaloids with bovine anterior pituitary D-2 dopamine receptors have been investigated with radioligand binding techniques and computer modeling procedures. Ergot alkaloids of the ergoline class are found to interact with the receptor in an agonist-specific fashion, exhibiting heterogeneous competition curves which can be resolved into high- and low-affinity components. In the presence of guanine nucleotides, however, only the low-affinity binding component is observable. In contrast, ergot alkaloids possessing a cyclic peptide side chain (ergopeptines) interact with the receptor in a homogeneous fashion, exhibiting competition curves which are monophasic and unaffected by guanine nucleotides. Ergopeptines thus display the binding characteristics of antagonist ligands even though they possess pharmacologically demonstrated agonist properties. These ergot alkaloid receptor binding characteristics determined from indirect competition experiments are also directly demonstrable using radiolabeled ergoline and ergopeptine ligands. The radiolabeled ergopeptine [3H]dihydroergocryptine ([3H]DHE) is shown to label identical binding sites with the same pharmacological characteristics as the antagonist [3H]spiroperidol. However, the dissociation rate of [3H]DHE from these binding sites is much slower than [3H]spiroperidol and is inconsistent with its equilibrium-determined binding affinity. In addition, saturation experiments with radiolabeled antagonists and agonists and unlabeled ergopeptines indicate that ergopeptines interact with these receptor sites in a competitive fashion. A model is presented which may explain these unique binding properties of ergot alkaloid agonists to the pituitary D-2 dopamine receptor.

Animals↗
PubMed1978

Distribution and accumulation of alkaloids in Catharanthus roseus G. Don during development.

Pattern of the total alkaloids distribution and accumulation in Catharanthus roseus G. Don was investigated during six different stages of flowering and fruiting. The highest concentration of alkaloids (mg perivine/g dry weight) was found in the roots at the start of flowering and the minimum in the stems during full fruiting stage; the rate of alkaloidal accumulation in the leaves, stems and roots tended to decrease during fruit maturation. The most active stage of alkaloidal biosynthesis was at the start of flowering in all vegetative organs. The maximum dry weights of leaves, stems and roots were obtained during the start of fruiting. The weights of flowers and fruits were relatively very small during different developmental stages. Harvesting Catharanthus roseus should best be carried out at the full-flowering stage to obtain the optimum yield of total alkaloidal content of leaves, stems and roots (as mg perivine/total dry weight of each organ per plant).

Plants, Medicinal↗
PubMed1982

Carcinogenic and mutagenic activity of an alkaloidal extract of Senecio nemorensis ssp. fuchsii.

The alkaloidal residue obtained after extraction of dried and pulverized Senecio nemorensis ssp. fuchsii contains two pyrrolizidine alkaloids, i.e. fuchsisenecionine and senecionine. In a chronic experiment doses of 8 mg/kg and 40 mg/kg b.w. of the alkaloidal extract were given five times a week by gavage to male and female Sprague-Dawley rats. The study was terminated after 114 weeks. Repeated serum analysis demonstrated a dose-related elevation of serum glutamic oxalacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and alkaline phosphatase (AP). Beside its hepatotoxic effect, the treatment proved to be hepatocarcinogenic, showing female rats to be more sensitive than males. Tumors diagnosed were of hepatocellular and angiogenic origin. In age-adjusted analysis the occurrence of these neoplasms revealed a clear dose-related trend (p less than 0.00005). In the in-vitro mutagenicity test system with V 79 Chinese hamster cells, the alkaloidal extract exerted a weak but dose-related mutagenic activity. Under the conditions used the alkaloidal extract of Senecio nemorensis ssp. fuchsii is a genotoxic carcinogen.

Alkaline Phosphatase↗
PubMed1993

Pharmacological characterization of N-substituted phenoxazines directed toward reversing Vinca alkaloid resistance in multidrug-resistant cancer cells.

Previously we reported the synthesis and partial characterization of 21 N10-substituted phenoxazines in reversing Vinca alkaloid resistance. Here we report on a subset of these compounds; we have compared their activities in increasing Vinca alkaloid accumulation and reversing drug resistance in KB-ChR8-5 and GC3/c1 (human colon carcinoma) cell lines. Results demonstrated that 1) N-substituted phenoxazines increase accumulation of vinblastine; 2) within this series, there is little correlation or ranking of activity between the two cell lines when Vinca alkaloid accumulation is compared at equal concentrations of modulator; 3) N-substituted phenoxazines demonstrate both quantitative and qualitative differences, compared with verapamil, a standard modulator; and 4) the series includes at least two compounds, 10-[3'-[N-bis(hydroxyethyl)amino]propyl]phenoxazine and 10-(N-piperidinoacetyl)phenoxazine, which increase Vinca alkaloid accumulation but do not significantly inhibit efflux. Additionally, certain of these multidrug resistance modulators significantly enhance accumulation (8-50-fold) of Vinca alkaloids in cell lines with very low or undetectable P-glycoprotein levels, where verapamil has little activity. It is concluded that at least part of the activity of some of these N-substituted phenoxazine modulators may be mediated through a P-glycoprotein-independent mechanism.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Effective dose in cattle of toxic alkaloids from tall larkspur (Delphinium barbeyi).

We determined the po toxicity of tall larkspur (Delphinium barbeyi) of known alkaloid composition to cattle. We calculated the effective dose at which the alkaloids methyllycaconitine and 14-deacetylnudicauline, collectively termed total toxic alkaloid, caused collapse and sternal recumbency. The effective dose of total toxic alkaloid that produced sternal recumbency in steers was 11.2 mg/kg bw. Based on this dose, we hypothesize that the LD50 for a po dose of total toxic alkaloids in cattle will be 25 to 40 mg/kg bw.

Aconitine↗