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[On the specificity of carbohydrate determination in proteins with the anthrone method].
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[Method of chemical analysis of the anthrone components of cascara sagrada].
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A comparison of analytic procedures for measurement of fractional dextran clearances.
Fractional dextran clearances have been extensively used to study glomerular size selectivity. We report on an analysis of different laboratory procedures involved in measuring fractional dextran clearances. The deproteinization of plasma samples by 20% trichloroacetic acid (TCA) revealed a protein contamination of 0.2% +/- 0.3%, whereas both 5% TCA and zinc sulfate deproteinization revealed a significantly higher remaining sample protein content (2.5% +/- 0.4% and 3.4% +/- 0.1%, respectively). Only zinc sulfate revealed incomplete deproteinization of urine samples (0.6% +/- 0.2%). Dextran recovery in plasma and urine supernatants was significantly lower after 5% TCA and zinc sulfate deproteinization when compared with 20% TCA deproteinization. Gel permeation chromatography (GPC) and high-performance liquid chromatography (HPLC) showed a variance of calibration smaller than 5% over 1 year. The use of 3 different sets of standard dextrans revealed significant differences in calibration. GPC and HPLC followed by anthrone assay showed a comparable variance in dextran concentration in plasma, from 3 to 6 nm (14% to 25%), whereas the variance in urine was lower for the GPC and anthrone assay, especially from 5.4 to 6 nm (23% to 43% versus 50% to 78%). HPLC and online refractometry showed the lowest variance of dextran concentration in plasma, from 3 to 6 nm (<4%), and in urine, from 3 to 5.2 nm (<7%), whereas it showed a higher variance in urine, from 5.4 to 6 nm, in comparison with GPC and HPLC with the anthrone assay. The GPC and anthrone assay revealed higher fractional dextran clearances in comparison with the HPLC and anthrone assay in healthy subjects (3 to 5.4 nm) as well as in patients with nondiabetic proteinuria (4.2 to 5.8 nm), and lower clearances in patients from 3 to 3.4 nm. The HPLC and anthrone assay revealed higher clearances in comparison with HPLC and online refractometry in healthy subjects (3.6 to 5.4 nm) and in patients (3.6 to 5.2 nm). The GPC and anthrone assay revealed characteristic differences in fractional dextran clearances between healthy subjects and patients. The HPLC and anthrone assay showed no significant differences between both groups, whereas HPLC and online refractometry showed only an increased clearance of dextrans from 4.6 to 5.2 nm in patients. Fractional clearances of dextran 5.6 nm as estimated by all 3 dextran assays were not significantly related to the fractional immunoglobulin G clearance or the immunoglobulin-to-albumin clearance index in our patients. Quantitative and qualitative differences in fractional dextran clearances may be induced by differences in laboratory procedures. We recommend sample preparation by 20% TCA deproteinization, frequent calibration with 1 set of dextran standards with low polydispersity, size-exclusion chromatography by GPC, and dextran detection by anthrone assay for optimal measurement of fractional dextran clearances. Even with such an approach, however, the variability in the measurement remains extremely high in the important range of dextrans greater than 5 nm.
Hydroxyl radical damage to DNA sugar and model membranes induced by anthralin (dithranol).
The antipsoriatic anthrones anthralin and butantrone caused degradation of the DNA sugar deoxyribose in the presence of ferric salt. The degradation was substantially inhibited by iron-binding hydroxyl radical scavengers, iron chelators, superoxide dismutase (SOD) and catalase, suggesting a mechanism in which antipsoriatic anthrones generate hydroxyl radicals via the Fenton reaction or an iron-catalysed Haber-Weiss reaction. Butantrone was markedly less efficient at generating hydroxyl radicals than anthralin. Using bovine brain phospholipid liposomes as model membranes to study the effects of antipsoriatic anthrones on lipid peroxidation, the peroxidation of liposomal membranes in the presence of ferric salt was maximally enhanced by anthralin and butantrone at 12.5 and 5 microM, respectively. Higher concentrations of the drugs resulted in less peroxidation. Chain-breaking antioxidants and iron chelators strongly decreased anthralin-enhanced lipid peroxidation, suggesting the involvement of hydroxyl, peroxyl or alkoxyl radicals. In contrast to their stimulatory effects on liposomal membrane peroxidation, both anthralin and butantrone diminished Fe3+/ascorbate-induced lipid peroxidation in liposomes. Butantrone was more effective as an inhibitor of lipid peroxidation than was anthralin. The antioxidant properties of antipsoriatic anthrones were determined in terms of their reactivities with the stable free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH). Antioxidant activity of antipsoriatic anthrones requires the presence of free hydroxyl groups at C-1 and C-8 and at least one hydrogen atom at C-10 of the anthrone nucleus. The role of active oxygen species produced by antipsoriatic anthrones and the biological effects on cellular targets are discussed with respect to the mode of action and manifestation of side effects of these drugs.
Characterization of skin tumor promotion and progression by chrysarobin in SENCAR mice.
The characteristics of the skin tumor promotion response with anthrone derivatives has been further examined in SENCAR mice. Chrysarobin (1,8-dihydroxy-3-methyl-9-anthrone) was an effective skin tumor promoter when applied twice weekly with dose-dependent increases in both papillomas and squamous cell carcinomas between 25 and 100 nmol/mouse. A similar dose-response relationship for papilloma and carcinoma formation was observed when chrysarobin was applied once weekly. Interestingly, chrysarobin was approximately twice as active as a skin tumor promoter when applied once weekly versus twice weekly. Doses of 25,100, and 220 nmol/mouse gave maximal papilloma responses of 2.90, 8.15, and 9.38 versus 0.73, 4.70, and 5.42 papillomas/mouse, respectively, in mice initiated with 25 nmol 7,12-dimethylbenz(a)anthracene. Thus, unlike 12-O-tetradecanoylphorbol-13-acetate (TPA), where a twice weekly application frequency is optimal, application of anthrone promoters such as chrysarobin once weekly is a more optimal frequency for papilloma development. Chrysarobin was also a much more effective skin tumor promoter when the start of promotion was delayed by an additional 10 weeks. Thus, groups of mice initiated with 10 nmol 7,12-dimethylbenz(a)anthracene and having promotion started in either the 3rd or the 13th week after initiation had maximal responses of 5.6 or 11.0 papillomas/mouse, respectively. In addition, the rate of papilloma development was faster in the delayed promotion group. The progression of papillomas to carcinomas was examined in all chrysarobin-treated groups and compared with three groups of mice treated with 3.4 nmol TPA. After 60 weeks of promotion, the anthrone promoter-treated groups had carcinoma:papilloma ratios 2.5 to 5.0 times higher than the TPA-treated groups. This was due primarily to the fact that similar carcinoma responses were observed in both anthrone- and TPA-treated mice at optimal promoting doses whereas the papilloma responses were significantly lower in the former groups. The data suggest that anthrone derivatives are very efficient tumor promoters. The results are further discussed in terms of mechanisms of skin tumor promotion.
Metabolism and pharmacokinetics of anthranoids.
Anthranoid derivatives are used all over the world as a treatment for constipation. These compounds are present in several drugs of plant origin, especially as O- or C-glycosides. Besides featuring different substituents, the aglycone might consist of an anthraquinone, an anthrone or a dianthrone. So far, detailed information concerning their metabolism and pharmacokinetic characteristics is available only in a few cases. The best characterized compounds are sennoside, a dianthrone O-glycoside present in senna leaves and senna pods, and its aglycone (rhein anthrone). After oral administration, sennoside is degraded only in the lower parts of the gastrointestinal tract, releasing its active metabolite rhein anthrone. Nowadays, this process is understood at the molecular level. A study with 14C-labelled rhein anthrone administered intracecally to rats, revealed that the compound is scarcely absorbed. Since on the contrary its anthraquinone equivalent is absorbed to a much larger extent, it is inferred that dianthrone- or anthrone-glycosides exhibit a lower systemic availability than anthraquinone O-glycosides.
Rational elimination of Aspergillus terreus sulochrin production.
Elimination of undesirable co-metabolites from industrial fermentations is often required due to the toxicities associated with the contaminants and/or due to difficulties in removing the contaminants during downstream processing. Sulochrin is a co-metabolite produced during the Aspergillus terreus lovastatin fermentation. Examination of the sulochrin biosynthetic pathway identifies the emodin anthrone polyketide synthase (PKS) at the origin. Thus, genetically disrupting the emodin anthrone PKS gene was expected to result in the elimination of sulochrin biosynthesis. To perform the disruption by homologous recombination, a fragment of the emodin anthrone PKS gene first needed to be isolated. Analysis of several reported fungal PKS amino acid sequences has identified three subfamilies of related sequences (called the Patulin subfamily, the Pigment subfamily, and the Reduction subfamily). PCR primers specific for the Pigment subfamily (of which the emodin anthrone PKS is expected to belong) were used to isolate a fragment of a novel PKS gene from A. terreus. Targeted gene disruption identifies the novel gene fragment as that from the emodin anthrone PKS. Consequently, the gene disruption event eliminated the production of metabolites from the sulochrin biosynthetic pathway.
Studies of aloe. III. Mechanism of cathartic effect. (2).
The mechanism of action of aloe-emodin-9-anthrone, a decomposition product of barbaloin, in causing a significant increase in the water content of the rat large intestine, was investigated. Aloe-emodin-9-anthrone inhibited rat colonic Na+, K(+)-adenosine triphosphatase (ATPase) in vitro, and increased the paracellular permeability across the rat colonic mucosa in vivo. Therefore, it seemed that the increase in water content of the rat large intestine produced by aloe-emodin-9-anthrone was due to both inhibition of absorption and stimulation of secretion without stimulation of peristalsis. Furthermore, pretreatment with loperamide, an antidiarrheal agent, completely prevented the increase of paracellular permeability induced by aloe-emodin-9-anthrone but did not completely reduce the concomitant increase in residual fluid volume. These findings suggest that aloe-emodin-9-anthrone has multiple mechanisms of action involved in the increase of water content in the rat large intestine.
[Purification, glucose-6-phosphate dehydrogenase inhibition, and HPLC analysis of four 1,8-dihydroxyanthrones].
With regard to the examination of their antipsoriatic properties, four 1,8-dihydroxyanthrones were prepared in a purity greater than 99%: Dithranol (1, anthralin) by chromatographic purification, chrysarobin (2) either by work-up from commercial chrysarobin or by an oxidative cleavage (FeCl3) of aloin, followed by a reduction (SnCl2/HCl) of the produced anthraquinone derivative (6), aloe emodin anthrone (3) by the action of aquous sodium tetraborate on aloin and frangula emodin anthrone (4) by the SnCl2/HCl-reduction of frangula emodin (7) isolated from the dry extract of the bark of alder buckthorn. UV/VIS, IR, 1H-NMR and mass spectra confirmed the structures of the four anthrones which all distinctly inhibited G-6-P dehydrogenase (0.05 mmol, desactivation in 6 h). For clinical studies the anthrones were incorporated into white petrolatum with exclusion of oxygen (under Ar). The anthrone content of the preparations was determined by HPLC (LiChrosorb RP-18, 7 microns [280 x 4 mm]; 1.5 ml/min MeOH/water/HOAc [80:20:0.2]) after extraction with CH2Cl2 (tR = 1: 10.4 min, 2: 15.3 min, 3: 4.7 min, 4: 7.7 min).
Defensive components in insect eggs: are anthraquinones produced during egg development?
Eggs of several insect species are protected against natural enemies by noxious components. However, almost nothing is known about the fate of these defensive substances during egg development nor their site of biosynthesis. The eggs of several leaf beetle species of the taxon Galerucini contain components that are unusual in insects: 1,8-dihydroxylated anthraquinones and anthrones that deter predators such as ants and birds. These components, i.e., the anthrones dithranol and chrysarobin, and the anthraquinones chrysazin and chrysophanol, are not sequestered from host plants. We asked whether the amounts of these components in the overwintering eggs of Galeruca tanaceti change from deposition to larval hatching. Gas chromatography-mass spectroscopy (GC-MS) analyses of eggs revealed a significant decrease in total amounts of dithranol and chrysophanol from egg deposition in autumn to the next spring 5 months later. Thus, these results do not provide any hint of active anthraquinone biosynthesis within eggs. Instead, the anthrones and anthraquinones that must be incorporated by the female into the eggs seem to be degraded to some extent either by the embryo or endosymbionts. GC-MS analyses showed that parasitization of eggs had some effects on the quantities of anthrones and anthraquinones.
Antithrombogenic pO2 sensor for continuous intravascular oxygen monitoring.
An antithrombogenic oxygen partial pressure sensor (Anthron pO2 sensor) was produced by coating a hydrophilic heparinized polymer (Anthron) on an etched epoxy composite ultramicroelectrode (microhole electrode). From in vitro tests, both the response time and stability were satisfactory under the conditions of a 20 microns thickness of Anthron coating and a depth up to 100 microns for the microhole. Additionally, results of in vitro tests without systemic heparinization demonstrated that a stable real time measurement of the intravascular oxygen partial pressure value was possible for a long period without thrombus formation or adhesion of blood components on the electrode surface of the Anthron pO2 sensor. Moreover, the measured data agreed with those from the blood gas analyser. Due to the thick thrombus formation on the electrode surface, the control (non-coated) sensor was unable to measure the intravascular oxygen partial pressure even for a short period of time.
Prenylated anthronoid antioxidants from the stem bark of Harungana madagascariensis.
Two new prenylated anthronoids, harunmadagascarins A and B, were isolated from the stem bark of Harungana madagascariensis along with six known compounds including two anthronoids: harunganol B and harungin anthrone, one benzophenone: methyl 3-formyl-2,4-dihydroxy-6-methyl benzoate and three pentacyclic triterpenes: friedelin, lupeol and betulinic acid. Harunmadagascarins A and B were characterized as 8,9-dihydroxy-4,4-bis-(3,3-dimethylallyl)-6-methyl-2,3-(2,2-dimethylpyrano)anthrone and 8,9-dihydroxy-4,4,5-tris-(3,3-dimethylallyl)-6-methyl-2,3-(2,2-dimethylpyrano)anthrone, respectively. The structures of these secondary metabolites were determined by spectroscopic means and comparison with the published data. Methyl 3-formyl-2,4-dihydroxy-6-methyl benzoate was isolated for the first time from a plant. Harunmadagascarins A and B, harunganol B and harungin anthrone exhibited significant antioxidant activity.
A new procedure for evaluation of renal function without urine collection in rat.
BACKGROUND: A new procedure to improve the accuracy of inulin assessment and renal glomerular filtration rate (GFR) avoiding urine sampling was compared and validated versus the reference procedure (with urine sampling and Anthrone reaction) in conscious unrestrained male Wistar rats. METHODS: The hemodynamic study consisted of a priming dose of inulin (16 mg/kg) and para-aminohippurate (PAH; 8 mg/kg) followed by an infusion of inulin (36 mg/mL) and PAH (5.8 mg/mL) at a rate of 0.055 mL/min until steady-state conditions were reached (105 min). Inulin concentrations from samples were determined by a new enzymatic assay and Anthrone reaction. PAH concentrations were determined according to the standard method described by Smith et al. RESULTS: A high correlation was found between GFR and renal blood flow (RBF) values calculated using the alternative (without urine sampling) and the reference (with urine sampling) clearance techniques (r = 0.98, P < 0.001, and r = 0.97, P < 0.001, respectively). Moreover, a significant and positive correlation between the values obtained from enzymatic and Anthrone inulin assessments was found (r = 0.99, P < 0.001). Likewise, the values of the 95% confidence interval (mean +/- 2 SD) for the enzymatic inulin assay showed a good agreement with those achieved with Anthrone (1.14 +/- 0.21 and 1.14 +/- 0.19 mL. min-1. 100 g-1 rat body weight, respectively). CONCLUSIONS: This new approach has methodological and experimental advantages with respect to traditional procedures, making it a useful tool, not only for research purposes but also in the clinical setting.
Inhibition of chrysarobin skin tumor promotion in SENCAR mice by antioxidants.
The present study was designed to further investigate the role of reactive oxygen species in the mechanism of action of anthrone tumor promoters. To accomplish this, the effects of several antioxidants on the induction of epidermal ornithine decarboxylase (ODC) activity, epidermal hyperplasia, skin edema, and skin tumor promotion by chrysarobin (1,8-dihydroxy-3-methyl-9-anthrone) were tested. Ascorbyl palmitate (AP), given 5 min prior to the promoter at 1 and 4 mumol doses, effectively inhibited the induction of ODC activity (28% and 59%, respectively) by 220 nmol of chrysarobin. Using a similar protocol, alpha-tocopherol acetate (alpha-TA) at 10 and 40 mumol doses also effectively inhibited the induction of ODC activity (36% and 70%, respectively) by 220 nmol of chrysarobin. In contrast, butylated hydroxyanisole (BHA) at doses up to 56 mumol per mouse was ineffective at inhibiting the induction of ODC by chrysarobin. AP at the 4 mumol dose significantly inhibited the induction of edema by chrysarobin by 24% and the induction of epidermal hyperplasia by 23%. alpha-TA at the 40 mumol dose also significantly inhibited chrysarobin-induced edema by 22% and epidermal hyperplasia by 17%. Skin tumor promotion in mice initiated with 25 nmol of 7,12-dimethylbenz[a]anthracene and promoted with once-weekly treatments of 220 nmol chrysarobin was markedly inhibited by treating mice with either AP or alpha-TA 5 min prior to promoter treatment. AP at 1 and 4 mumol doses significantly reduced the number of papillomas per mouse, by 48% and 44%, respectively. alpha-TA at 10 and 40 mumol doses also significantly reduced the number of papillomas per mouse, by 33% and 59%, respectively. In two separate tumor experiments, BHA at 2.8 and 5.6 mumol failed to inhibit chrysarobin tumor promotion. The current results provide further support for a role of reactive oxygen species in the tumor promoting activity of anthrones. In addition, the data indicate that the phenolic antioxidant BHA is an ineffective inhibitor of anthrone tumor promotion.
Studies of aloe. V. Mechanism of cathartic effect. (4).
Aloe-emodin-9-anthrone(AE-anthrone), produced from barbaloin in the rat large intestine, caused not only an increase in the intestinal water content but also stimulated mucus secretion. This might play an important role in the occurrence of diarrhea. It was demonstrated that the amount of AE-anthrone produced in the rat large intestine(maximal amount: 568 micrograms/rat at 4 h after injection) was enough to cause both of these effects, which were observed following intracecal administration of barbaloin (31.1 mg/kg). These results together with our previous data, which showed a relationship between increase in the intestinal water content and the stimulation of peristalsis, confirm that AE-anthrone is the principal agent responsible for the cathartic effect of barbaloin. We also propose that the increase in water content is a more important factor than stimulation of peristalsis in the induction of diarrhea by barbaloin.
Anthranoids and the mucosal immune system of the colon.
The mechanism of action of anthranoids in general and of sennosides at the cellular level is not precisely known. Pseudomelanosis or pseudolipofuscinosis, a condition characterized by the accumulation of pigmented macrophages in the lamina propria, is one of the well-known effects of these products. It is most probably the result of an interaction between apoptotic epithelial cells and the lamina propria cellular infiltrate. Treatment of cell suspensions of intestinal epithelial cells and of human intestinal epithelial cells in culture with rhein anthrone, the active compound of sennosides, demonstrates a direct influence of the drug on these epithelial cells. Low doses induce alterations in cellular shape and organelles consistent with increased metabolism. High doses induce apoptotic changes. The interaction between the epithelial cells and cells of the monocyte/macrophage lineages induces also the release of prostaglandins of the E series as shown by experiments on cell cultures of epithelial cells and peripheral blood cells. An increase of PGE2 release to about 140% of the control value is noted following administration of low doses of rhein anthrone to a combination of human intestinal epithelial cells and human peripheral blood mononuclear cells. This finding indicates that rhein anthrone is activating cellular components of the intestinal immune system and may by this pathway induce secretion and motility.
The metabolism of anthranoid laxatives.
The anthranoid compounds, which chemically can be described as dihydroxy-anthraquinones, -dianthrones and -anthrones, possess a laxative effect. As these substances are the constituents of some plants and their extracts, they are often referred to as vegetable laxatives. If present in the glycoside form, these compounds represent unique targeting molecules; after oral administration they are carried, unabsorbed, to the large intestine, where the active aglycon is released by bacterial hydrolysis of the sugar. The intestinal bacterial flora also accounts for the reduction of anthraquinone aglycons to the corresponding anthrones. After absorption, the anthranoids are transformed mainly to their corresponding glucuronide and sulfate derivatives, which appear in urine and bile. Experiments with radiochemical anthranoids showed a significant clearance of tissue-bound activity of all organs, except the kidneys, which exhibited a pronounced retention of anthranoid equivalents. It is argued that therapy with anthrone C-glycosides (present, for example, in cascara) or dianthrone O-glycosides (present for example, in senna) is preferable therapy with anthraquinones, as the anthranoid moiety of the former seems to be substantially less readily absorbed from the gastrointestinal tract.