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The anthelmintic activity of the drupe extracts of Melia azedarach L. (Meliaceae) growing in Argentina was tested against tapeworms, hookworms, nodular worms and earthworms, and was shown to be better than the standards piperazine phosphate and hexylresorcinol against tapeworms and hookworms, respectively.
Effects of piperazine derivatives, especially of diethylcarbamazine (DEC) on adult Angiostrongylus cantonensis and Dirofilaria immitis were examined. Piperazine (3 X 10(-5)-10(-4) M) paralyzed A. cantonensis and the action was antagonized by picrotoxin. 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) (10(-5)-10(-4) M) caused contraction but little effect was produced by strychnine. An inhibitory effect on untreated preparations was caused by lower concentrations (3 X 10(-6)-10(-5) M) of diethylcarbamazine citrate (DEC) and also on the preparations contracted by eserine. A stimulatory effect was also seen when higher concentrations (10(-4)-3 X 10(-4) M) of this drug were applied to both preparations. The inhibitory action of DEC was antagonized by gabergic antagonists such as picrotoxin and bicuculline, but not by alpha-adrenergic antagonists like dibenamine and phentolamine. When the worm preparation was paralyzed by strychnine or hexylresorcinol (inhibitors of the release of acetylcholine in this worm), the stimulatory effect of DEC was blocked, but pyrantel (a nicotinic cholinergic agonist) contracted the paralyzed preparation. However, the effect of DEC on D. immitis (10(-7)-3 X 10(-4) M) was inhibitory, and this action was also antagonized by picrotoxin. These results suggest that the DEC inhibitory and stimulatory action is through the gabergic and cholinergic mechanisms in adult A. cantonensis and D. immitis.
The amebicides dehydroemetine and chloroquine diphosphate and the anthelmintic pyrvinium pamoate, previously reported to be mutagenic in Salmonella typhimurium (Cortinas de Nava et al., 1983), were clearly shown to be genotoxic in the Escherichia coli pol A+/pol A- assay. Two other antiparasitic drugs, diiodohydroxyquin and 4-hexylresorcinol, were also found to be genotoxic in E. coli, while iodochlorhydroxyquin preferentially inhibited the pol A+ strain. From the 3 alternative testing methods employed, the liquid suspension succeeded in detecting 5 antiparasitic drugs as genotoxic; the microsuspension identified 2, and the disc diffusion method only 1. However, the metabolic activation system could only be coupled successfully and in a reproducible way to the microsuspension assay.
The present study demonstrates the antiradical efficiency of fisetin, a flavonol widely distributed in fruits and vegetables, by its ability to react with two different free radicals, ABTS; and DPPH;. The polyphenolic nature of fisetin led us to consider whether it might be oxidised by polyphenol oxidase (PPO), and the results reported show that it can be oxidised by PPO extracted and partially purified from broad bean seeds. The reaction was followed by recording spectral changes with time, with maximal spectral changes being observed at 282 nm (increase in absorbance) and at 362 nm (decrease). The presence of two isosbectic points (at 265 and 304 nm) suggested that only one absorbent product was formed. These spectral changes were not observed in the absence of PPO. The oxidation rate varied with the pH, reaching its highest value at pH 5.5. The fisetin oxidation rate increased in the presence of sodium dodecyl sulfate, an activator of polyphenol oxidase. Maximal activity was obtained at 0.87 mM sodium dodecyl sulfate. The following kinetic parameters were determined: Vmax=49 microM/min, Km=0.6 mM, Vmax/Km=8.2x10-2 min-1. Flavonol oxidation was inhibited by selective PPO inhibitors such as cinnamic acid (a classical competitive inhibitor, Ki=1.4 mM) and 4-hexylresorcinol, which behaved as a slow-binding inhibitor. The results reported show that fisetin oxidation was strictly dependent on the presence of polyphenol oxidase.
An unusual intestinal infection with the parasite Metagonimus yokogawai was acquired by an American traveling in the Orient. Diarrhea began abroad, and recurred at intervals until she was seen 1 1/2 years later. Stool examinations resulted in the recovery of small operculated ova characteristic of intestinal or biliary fluke infection. Treatment with hexylresorcinol failed to eradicate the infection, but subsequent use of tetrachloroethylene was successful and facilitated recovery of adult parasites, leading to the specific diagnosis of metagonimiasis. Metagonimiasis and related intestinal fluke infections should be considered as a possible cause of persistent diarrhea in travelers returning from endemic areas abroad.
Adult roundworms (Ascaris lumbricoides) obtained from pigs were suspended in modified Tyrode solution at 37 degrees in fine nylon stockings, and the movements of the stockings were recorded. This method of suspension avoided damage to the cuticle or occlusion of the alimentary tract of the worm.Piperazine salts caused gradual narcosis, the time of onset of which was related linearly to the logarithm of the concentration of drug in the bath. The method is suitable for the assay of preparations of piperazine. Tetrachlorethylene, hexylresorcinol, and oil of chenopodium all caused stimulation of movement before the worm was immobilized. Santonin caused incoordination of the movements of the anterior end of the worm; the movements of the body were apparently unaffected. Piperazine is the safest preparation available for the treatment of ascariasis.
Several phenols known to be antiseptics were tested in vitro for their ability to adsorb to saliva-coated enamel and subsequently inhibit plaque formation. 3,5,4'-tribromosalicylanilide was found to be effective against growth and plaque formation of A viscosus, A naeslundii, S mutans and S sanguis. Dibromsalicil was effective against A viscosus. The other phenols (hexylresorcinol, thymol, phenylphenol and zinc phenolsulfonate) did not inhibit in vitro growth or plaque formation.
The mutagenic activity of chemical analogues of microbial anabiosis autoinducers (the autoregulatory d1 factors of cell differentiation), which act to inhibit cell proliferation, to enhance cell tolerance, and to induce the transition of cells to anabiotic state, was studied using the Ames test. In the range of concentrations studied (0.1 to 100 micrograms/ml), alkyl-substituted hydroxybenzenes (AHBs) differing in hydrophobicity, i.e., methylresorcinol (C1-AHB) and hexylresorcinol (C6-AHB), as well as unsubstituted resorcinol, showed different growth-inhibiting and mutagenic effects. C6-AHB was found to inhibit the growth of Salmonella typhimurium TA100 and to induce its mutagenesis at a rate of 1.8 revertants/nmol. C1-AHB taken at low concentrations not only failed to inhibit bacterial growth but even stimulated it and exerted an antimutagenic effect. Unsubstituted resorcinol virtually did not influence bacterial growth and showed weak mutagenic activity. The growth-inhibiting effect of elevated C6-AHB concentrations correlated with the degree of the transition of the original phenotype producing S-type colonies to a phenotype producing R-type colonies. The role of AHB homologues, as microbial autoregulators with mutagenic activity, in the regulation and correlation of two processes (the phenotypic dissociation of microbial populations and the formation of resting microbial forms) is discussed. The accumulation of AHBs in senescent microbial cultures may induce adaptive mutations, change the expression of genes, and promote the development of minor cell subpopulations (phenotypes), thus providing for the adaptation of these cultures to varying environmental conditions.
The microbial alkylhydroxybenzenes (AHB), autoinducers of anabiosis, or d1 factors, participate in stress response of mycelial fungi, as determined from changes in intracellular Ca2+ concentration. By using the genetically modified strain Aspergillus awamori 66A, which produces a recombinant Ca2+-dependent protein aequorin, the dynamics of Ca2+ was studied in the cytosol of cells exposed to mechanical shock in the presence of the protective doses (0.001-0.01% w/vol) of a chemical AHB analogue, 4-n-hexylresorcinol. Like under stressful conditions, Ca2+ concentration increases in the cell cytosol in response to enhanced AHB level in a growing fungal culture; thus, AHB is perceived by cells as a stress signal. The level of cell response, which was determined from the amplitude of luminescence dependent on the Ca2+ concentration in cytosol was related to the physiological age of the cells and AHB concentration. Micromycete preincubation with AHB was found to protect cells from subsequent stress; this was reflected in the Ca2+ response. The protective AHB effect was manifested as (1) a significant decrease in the amplitude of luminescence and, thus, in Ca2+ accumulation in the cytosol during subsequent mechanical stress (as compared to the control--mechanical stress only); (2) development of the secondary Ca2+ response, which was not observed in the control; (3) a high level of Ca2+ retained in the cytosol for a long time in the presence of AHB (as compared to the control without preincubation with AHB). The mechanisms underlying the AHB effect on the Ca2+ transport systems are discussed.
We established that chemical analogues of alkylhydroxybenzenes (AHB), belonging to alkylresorcinols and functioning as microbial autoregulatory d1 factors, enhance the UV resistance of various DNA molecules of different origin and conformation. These include the linear DNA of the lambda phage, bovine spleen DNA, and the DNA of the pUC19 plasmid that is composed of a number of annular (supercoiled and relaxed) and linearized molecules. Irradiating DNA with UV light (lambda = 254 nm) in the presence of methylresorcinol (MR) or hexylresorcinol (HR) results in comparatively insignificant DNA destruction as evidenced by our data on the electrophoretic mobility pattern in agarose gel. Using the linear Hind III restricts of the lambda phage DNA, we revealed that the protective effect of AHB varies depending on their chemical structure (it is more manifest with HR than MR) and concentration. Importantly, the effect of HR on bovine spleen DNA was based on its protective activity and manifested itself after a long incubation period. Studies using the pUC19 plasmid demonstrated that AHB, apart from increasing the resistance of linearized DNA molecules to UV irradiation, prevented both the supercoiled annular-supercoiled relaxed and the supercoiled relaxed-linearized transitions. The possible mechanisms of the UV-protective effect of AHB on DNA and their contributions to the resistance of dormant microbial forms to environmental factors are discussed.
The efficacy of a leukemia cell transplant model to measure potential chemotherapeutic activity was tested with five different chemicals that had previously been evaluated in 2-year studies. Leukemic spleen cells from Fischer rats were injected subcutaneously into syngeneic recipients and the effects of chemical treatment on tumor progression were evaluated at 70 days post-transplant. The data from the short-term assay were in all cases correlated with the trends reported for mononuclear cell leukemia in 2-year studies, where two chemicals were reported to decrease the incidence and three chemicals were reported to increase the incidence of leukemia. Short-term treatment with the two chemicals which caused negative trends for leukemia (2-ethoxyethanol or ethylene glycol monoethyl ether; 4-hexylresorcinol) delayed and/or reduced tumor growth in the transplant model in a dose-related fashion, as exhibited by reduction or elimination of splenomegaly and leukoblastosis, and a reversal in the depression of red blood cell indices or platelet counts. By contrast, the rate of tumor progression was increased in the short-term assay of the three chemicals which previously caused increased trends for leukemia in 2-year studies (pyridine; 2,4,6-trichlorophenol, dichlorvos). The severity of the mononuclear cell leukemia in the transplant recipients, as measured by histopathological examination of spleen and liver, was correlated with the changes in tumor growth rates. The in vivo leukemia transplant model is a short-term assay that could be used to screen a variety of potential chemotherapeutic agents, or to study structure-activity relationships within one class of chemicals.
4 amebicides (chloroquine diphosphate, diiodohydroxyquin, iodochlorohydroxyquin and dehydroemetine) and 6 anthelmintics (bephenium hydroxynaphthoate, 4-hexylresorcinol, mebendazole, niclosamide, pyrantel pamoate and pyrvinium pamoate) were tested for mutagenicity in the Salmonella typhimurium microsomal test system. Frameshift mutations were induced by dehydroemetine and niclosamide following activation by microsomal enzymes, while pyrvinium pamoate induced both frameshift and base-pair substitution mutations with or without metabolic activation. The urine of mice treated with dehydroemetine or pyrvinium pamoate showed no mutagenic activity. However, urine obtained from mice treated with niclosamide was mutagenic in strains TA98 and TA1538. The fluctuation assay showed chloroquine diphosphate to be mutagenic in TA1537, a strain which detects frameshift mutations.
R. S. Chhabra, J. Haseman, A. Hall, and C. Baskin (Fundam. Appl. Toxicol. 11, 685-690, 1988) have raised the question of whether the apparent antitumorigenic effect of 4-hexylresorcinol suggests its possible use as an antineoplastic agent. In response to that paper, it is noted that over 20% of the compounds subjected to the "carcinogenesis" bioassay of the NCI/NTP program show apparent antitumorigenic effects of a similar sort. A thought experiment is proposed that shows that any compound subjected to these test conditions should produce a shift in patterns of tumors, regardless of whether the compound is a true "carcinogen" or a true "antineoplastic" agent. This thesis is illustrated with an alternative statistical analysis of six AZO dye studies that were conducted in the same lab during the same period, and the existence of apparent effects for three other other relatively innocuous substances is noted. Short-term experiments are proposed to test this thesis. Finally, the implications of this thesis on the interpretation of "carcinogenesis" bioassays is examined.
Polyphenol oxidase (PPO) was isolated from the B-serum obtained after repetitive freeze-thawing of the bottom fraction isolated from ultracentrifuged fresh latex. The B-serum was subjected to acetone precipitation and CM-Sepharose chromatography, affording two PPOs, PPO-I and PPO-II, which, upon SDS-PAGE, were 32 and 34 kDa, respectively. Both PPOs possessed the same pI (9.2), optimum pH (7) and optimum temperature (35-45 degrees C). They are stable up to 60 degrees C and active at broad pH ranges from 4-9. The K(m) values of PPO-I for dopamine, L-dopa and catechol as substrates are 2.08, 8.33 and 9.09 mM, while those for PPO-II are 2.12, 4.76 and 7.14 mM, respectively. Among various PPO inhibitors tested, 4-hexylresorcinol was the most potent. Anionic detergents were among the most effective activators of the enzymes, while cationic and nonionic detergents showed little and no effect on the PPO activities, respectively.
Polyphenol oxidase (PPO) from eggplant was extracted and partially purified by a two-step fractionation-precipitation using ammonium sulfate and phenylsepharose hydrophobic interaction chromatography. The eggplant PPO extract was characterized concerning its kinetic properties. Optimal conditions to obtain Maillard reaction products (MRPs) with a maximal inhibitory potency (IP) toward PPO activity were determined using the surface response methodology and a four-factor and five-level experimental design. The MRPs were prepared from cysteine (0.25 M) and glucose (0-1 M), at several initial pH values (2-6) and at differing heating times (3-19 h) and temperatures (95-115 degrees C). The maximal IP was obtained after heating a model system of glucose/cysteine (1/0.25 M) at pH 2 for 3 h 20 min at 115 degrees C. The soluble part of this MRP, called MRP(IPmax), was a noncompetitive inhibitor toward eggplant PPO. The IP of MRP(IPmax) on PPO activity was very potent as compared to that displayed by benzoic, p-coumaric, and t-cinnamic acids, as well as sorbic acid and 4-hexylresorcinol. The activity of preincubated PPO at 0 degrees C with MRP(IPmax) was only slightly restored after dialysis or gel filtration.
Because direct oxidation of flavonols by polyphenol oxidase (PPO) has not previously been reported and, given the importance of flavonols, the ability of broad bean seed PPO to oxidize the flavonol quercetin was studied. The reaction was followed by recording spectral changes with time. Maximal spectral changes were observed at 291 nm (increase) and at 372 nm (decrease). The presence of two isosbectic points (at 272 and 342 nm) suggested the formation of only one absorbent product. These spectral changes were not observed in the absence of PPO. The oxidation rate, which varied with pH, was highest at pH 5.0. The following kinetic parameters were also determined: V(m) = 11 microM/min, K(m) = 646 microM, V(m)/K(m) = 17 x 10(-)(2) min(-)(1). Flavonol oxidation was efficiently inhibited (K(I) = 3.5 microM) by specific PPO inhibitors such as 4-hexylresorcinol. The results obtained showed that quercetin oxidation was strictly dependent on the presence of PPO.
Prevention of browning of apples slices has been difficult to achieve because of the rapidity of the enzymatic oxidation of phenolic substrates even under reduced atmospheric pressure storage. Combinations of enzymatic inhibitors, reducing agents, and antimicrobial compounds containing calcium to extend storage life were tested to decrease the browning of Red Delicious apple slices stored at 5 and 10 degrees C under normal atmospheric conditions. Treatments were devised to prevent browning for up to 5 weeks at 5 degrees C with no apparent microbial growth using dipping solutions of compounds derived from natural products consisting of 4-hexylresorcinol, isoascorbic acid, a sulfur-containing amino acid (N-acetylcysteine), and calcium propionate. Analyses of organic acids and the major sugars revealed that the slices treated with the combinations of antibrowning compounds retained higher levels of malic acid and had no deterioration in sugar levels at 5 and 10 degrees C, indicating that higher quality was maintained during storage.
In the present paper the catecholase and cresolase activities of eggplant polyphenol oxidase (PPO) are described. To preserve the latter activity, a partially purified enzyme was used. Peroxidase was removed from the preparation to avoid its interference with PPO during phenol oxidation. The partially purified eggplant PPO was fully active. The catecholase/cresolase ratio of 41.1 indicated that, in a pH close to the physiological, diphenol oxidation predominates over monophenol oxidation. The characteristic lag phase of the cresolase activity is modulated by the pH, the monophenol and diphenol concentrations, and the enzyme's concentration. The effect of several inhibitors was also tested, and the K(i) values of the two most effective (tropolone and 4-hexylresorcinol) were determined.