Quantitative in vitro assessment of drug phototoxicity by a chemiluminescence method.
(9/133)
OBJECTIVE: To establish a test model for phototoxic agents using the method of chemiluminescence. METHODS: The phototoxicity of pipemidic acid, doxycycline, griseofuvin and chlorpromazine was detected. These agents and distilled water were irradiated with ultraviolet A (UVA) in the presence of nicotinamide adenine dinucleotide reduced (NADH), and the duplicated samples were incubated in the dark as dark controls. Then luminol was added to the test samples, and the chemiluminescent value was counted and calculated. RESULTS: Chemiluminescent values of pipemidic acid, doxycycline and griseofuvin were significantly higher than those in controls. The result of linear regression analysis showed that phototoxic intensity was linear correlated with UVA dosage. The regression coefficient for distilled water was 0.56, indicating that the luminescent value (LV) rose slightly after UVA irradiation. For pipemidic acid, griseofuvin and doxycycline, the regression coefficients reached 76.96, 254.33 and 92.61 respectively, significantly increased in comparison with those of negative controls (P < 0.01). CONCLUSION: Phototoxicity of pipemidic acid, doxycycline and griseofuvin can be detected with the method of chemiluminescence. (+info)
Mycotoxin-producing potential of mold flora of dried beans.
(10/133)
To evaluate the potential for mycotoxin production by molds in dried beans, the mold flora of 114 samples was determined both before and after surface disinfection of the beans with 5% NaOCl. Surface disinfection substantially reduced mold incidence, indicating that contamination was mainly on the surface. The flora, both before and after disinfection, was dominated by species of the Aspergillus glaucus group, the toxicogenic species A ochracues, Penicillium cyclopium, and P. viridicatum, and species of Alternaria, Cladosporium, and Fusarium. The toxicogenic species Aspergillus flavis, A. versicolor, Penicillium Citrinum, P. expansum, P. islandicum, and P. urticae were encountered less frequently. Of 209 species of Aspergillus and Penicillium screened for mycotoxin production on sterile rice substrate, 114 produced one or more of the following mycotoxins: A. flavus, aflatoxins; A. ochraceus, ochratoxins; A. nidulans, A. unguis, and A. versicolor, sterigmatocystin; P. cyclopium, penicillic acid; P. citrinum and P. viridicatum, citrinin; P. urticae, patulin and griseofulvin. Sterigmatocystin production by A. unguis is reported for the first time. (+info)
Griseofulvin induces mitotic delay and aneuploidy in bone marrow cells of orally treated mice.
(11/133)
Griseofulvin (GF) is a fungicide drug well characterized for its aneugenic activity in vitro. In vivo strong evidence of aneuploidy and polyploidy induction has been obtained in germ cells, especially in oocytes. More controversial are the data on the aneugenicity of griseofulvin in somatic cells. In this paper we provide evidence that GF induces non-disjunction and cell cycle delay in bone marrow cells of orally treated mice. Adult female mice were administered olive oil suspensions of 200, 666 or 2000 mg/kg GF by gavage and killed 18 or 24 h later. To minimize animal-to-animal variation in the absorption and distribution of GF, mice were fasted from the time of GF administration to the time of killing. Two hours before treatment the animals were s.c. implanted with a bromodeoxyuridine tablet to obtain differential chromatid staining and to determine the number of divisions after GF treatment for each metaphase. Mitostatic effects of GF were assessed by the relative proportions of first, second and third generation metaphases and the average generation time (AGT) method. A statistically significant increase with respect to the control AGT value was observed after treatment with 666 and 2000 mg/kg, suggesting that GF, as already shown in meiosis, interfered with cell cycle progression. Hyperploidy was scored in second generation metaphases. Eighteen hours after treatment, the frequencies of hyperploid cells were significantly (P < 0.05) higher in all GF-treated groups than in their matched control group. The effect was not dose-dependent. No further increase in aneuploidy was observed at 24 h, suggesting that cells overcoming mitotic arrest did not have a higher rate of non-disjunction. No induction of polyploidy was demonstrated. We conclude that GF induces mitotic delay and aneuploidy in mouse bone marrow and suggest that the protocol used to formulate the gavage suspensions and the after-treatment fasting of the animals enhanced the bioavailability of GF to bone marrow cells. (+info)
Differential binding of methyl benzimidazol-2-yl carbamate to fungal tubulin as a mechanism of resistance to this antimitotic agent in mutant strains of Aspergillus nidulans.
(12/133)
The antimitotic compound methyl benzimidazol-2-yl carbamate (MBC) formed a complex in vitro with a protein present in mycelial extracts of fungi. The binding protein of Aspergillus nidulans showed a set of properties which is unique for tubulin. Binding occurred rapidly at 4 degrees C and was competitively inhibited by oncodazole and colchicine. Other inhibitors of microtubule function such as podophyllotoxin, vinblastine sulfate, melatonin, and griseofulvin did not interfere with binding of MBC. Electrophoretic analysis of partially purified preparations of the binding protein revealed the presence of proteins with similar mobilities as mammalian tubulin monomers. Hence it is concluded that the binding protein is identical with fungal tubulin. The effect of MBC on mycelial growth of mutant strains of A. nidulans was positively correlated with the affinity of the binding sites for this compound. The apparent binding constant for MBC and tubulin from a wild type was estimated at 4.5 X 10(5), from a resistant strain at 3.7 X 10(4), and from a strain with increased sensitivity to MBC at 1.6 X 10(6) liters/mol. Mutants showing resistance and increased sensitivity to MBC are candidates to have alterations in tubulin structure. Affinity of tubulin for MBC is probably a common mechanism of resistance to this compound in fungi. Low affinity of tubulin for MBC is probably a common mechanism of resistance binding constant of 2.5 X 10(3) liters/mol. (+info)
Chemosensory responses of a protozoan are modified by antitubulins.
(13/133)
Modification of a behavioral response of a marine dinoflagellate to chemical cues is described. Negative response to choline was modified by the antitubulins vincristine, vinblastine, griseofulvin, and trifluralin, but not by colchicine. Positive responses to 3,4-dihydroxyphenylalanine were unaffected by these drugs. (+info)
Formation of Mallory body-like inclusions and cell death induced by deregulated expression of keratin 18.
(14/133)
Mallory bodies (MBs) are cytoplasmic inclusions that contain keratin 8 (K8) and K18 and are present in hepatocytes of individuals with alcoholic liver disease, nonalcoholic steatohepatitis, or benign or malignant hepatocellular neoplasia. Mice fed long term with griseofulvin are an animal model of MB formation. However, the lack of a cellular model has impeded understanding of the molecular mechanism of this process. Culture of HepG2 cells with griseofulvin has now been shown to induce both the formation of intracellular aggregates containing K18 as well as an increase in the abundance of K18 mRNA. Overexpression of K18 in HepG2, HeLa, or COS-7 cells also induced the formation of intracellular aggregates that stained with antibodies to ubiquitin and with rhodamine B (characteristics of MBs formed in vivo), eventually leading to cell death. The MB-like aggregates were deposited around centrosomes and disrupted the microtubular array. Coexpression of K8 with K18 restored the normal fibrous pattern of keratin distribution and reduced the toxicity of K18. In contrast, an NH(2)-terminal deletion mutant of K8 promoted the formation of intracellular aggregates even in the absence of K18 overexpression. Deregulated expression of K18, or an imbalance between K8 and K18, may thus be an important determinant of MB formation, which compromises the function of centrosomes and the microtubule network and leads to cell death. (+info)
Use of gene networks from full genome microarray libraries to identify functionally relevant drug-affected genes and gene regulation cascades.
(15/133)
We developed an extensive yeast gene expression library consisting of full-genome cDNA array data for over 500 yeast strains, each with a single-gene disruption. Using this data, combined with dose and time course expression experiments with the oral antifungal agent griseofulvin, whose exact molecular targets were previously unknown, we used Boolean and Bayesian network discovery techniques to determine the gene expression regulatory cascades affected directly by this drug. Using this method we identified CIK1 as an important affected target gene related to the functional phenotype induced by griseofulvin. Cellular functional analysis of griseofulvin showed similar tubulin-specific morphological effects on mitotic spindle formation to those of the drug, in agreement with the known function of CIK1p. Further, using the nonparametric, nonlinear Bayesian gene networks we were able to identify alternative ligand-dependant transcription factors and G protein homologues upstream of CIK1 that regulate CIK1 expression and might therefore serve as alternative molecular targets to induce the same molecular response as griseofulvin. (+info)
Treatment of superficial fungous infections. Value and limitations of systemic administration of griseofulvin.
(16/133)
Comprehensive studies and numerous clinical reports have shown that griseofulvin orally in a dose of 1 gm. daily is an effective treatment for superficial fungous infections of the skin, hair and nails. The drug is not effective against yeast infections (moniliasis), bacterial infections or most of the deep fungous infections. Duration of treatment varies with the site of infection, glabrous skin, crotch and scalp responding within four to five weeks. Infections of palms, soles and nails require a considerably longer time, palms healing more quickly than soles and fingernails more quickly than toenails, which may require up to a year of continuous treatment. Auxiliary measures such as clipping hair, removing infected nail tissue and topical fungicides shorten the duration of treatment. No serious side effects have been reported. Minor discomforts such as headaches and mild rashes occur in some cases. Observations of a series of 49 patients with superficial fungous infections, especially hand, foot and nail infections due to Trichophyton rubrum, confirmed these reports taken from the literature. Attempts to use a reduced dosage schedule did not prove satisfactory. (+info)