Griseofulvin

Luigi De Carli, Lidia Larizza

Research output: Contribution to journalArticle

Abstract

Griseofulvin (GF) is a mycotoxin produced by various species of Penicillium including P. griseofulvum Dierckx, P. janczewski (P. nigricans) and P. patulum. It is active against dermatophytic fungi of different species in the genera Microsporum, Trychophyton and Epidermophyton. Because of its capacity to concentrate in the keratinous layer of the epidermis and its relatively low toxicity in man, it has been extensively used in the therapy of dermatophytoses by oral administration. The biological activity of GF towards fungi is manifested as nuclear and mitotic abnormalities followed by distortions in the hyphal morphology. Mitotic segregation is also induced in fungi by GF treatment. In higher eukaryotes the cytostatic action of GF is essentially due to a mitotic arrest at late metaphase/early anaphase. The cytological effects observable both in vivo and in vitro on different plant and animal cell systems, include C-mitoses, multipolar mitoses and multinuclearity. Prolonged GF treatment in experimental animals provokes biochemical changes consisting mainly of disturbances of porphyrin metabolism, variation in the microsomal cytochrome levels and formation of Mallory bodies. In mice these alterations are followed by the development of multiple hepatomas. Evidence of tumor induction by GF has been obtained in mice and rats, but not in hamsters. GF may also act either as a promoting or a co-carcinogenic agent, depending on the circumstances of its administration. It has been found to increase the frequency of cell transformation induced by polyoma virus, but not to induce cell transformation per se. Induction of sperm abnormalities has been observed in GF-treated mice. The embryotoxic and teratogenic action of GF has been demonstrated in pregnant rats exposed during organogenesis. Genetic effects of GF have been investigated by the following tests: Salmonella/microsome mutagenicity assay, point mutations in mammalian and plant cells, DNA damage and repair, SCE, chromosome aberrations, micronuclei, dominant lethals, aneuploidy in lower and higher eukaryotes. A positive response has been obtained in the assays on numerical chromosome changes in all the systems analyzed; limited or inconclusive evidence has been obtained for SCE and structural chromosome changes. Doubled or highly polyploid sets can be detected in all types of cells during or immediately after GF treatment. A marked increase in chromosome number variation is observed at various times after withdrawal of the drug, with prevailing hyperdiploid and reduced sets in animal cells and plant cells respectively. Closely related to the effect on chromosome number is the ability of GF to increase the frequency of segregants for selected genetic markers in different cell systems either in the presence or in the absence of mutagenic treatment. The mode of action of GF on mitotic spindle microtubules (MTs) has been analyzed in comparison with other known antitubulins. Unlike colchicine and Vinca alkaloids GF causes a reduction or disruption of MTs, in relation to the dose, by inhibiting their combination with the microtubule-associated proteins (MAPs). Evidence in favor of this kind of interaction is provided by the results of studies on GF-resistant mutants in mammalian cells. In view of its unique properties as a microtubule-disorganizing agent, its capacity to induce chromosome malsegregation in a variety of organisms either in vivo or in vitro and its specific effects on liver metabolism, GF may be considered a valuable research antibiotic. Major reservations on its therapeutic use seem to be justified when considering the positive response to carcinogenicity and teratogenicity tests in animals and the chromosome effects observed both in vivo and in vitro.

Original languageEnglish
Pages (from-to)91-126
Number of pages36
JournalMutation Research - Reviews in Genetic Toxicology
Volume195
Issue number2
DOIs
Publication statusPublished - 1988

Fingerprint

Griseofulvin
Chromosomes
Plant Cells
Animals
Fungi
Microtubules
Polyploidy
Cells
Eukaryota
Mitosis
Metabolism
Rats
Assays
Mallory Bodies
Epidermophyton
Carcinogenicity Tests
Plant DNA
Vinca Alkaloids
Microsporum
Polyomavirus

Keywords

  • Dermatophytic fungi
  • Epidermis
  • Griseofulvin
  • keratinous layer
  • Mycotoxin
  • Penicillium species

ASJC Scopus subject areas

  • Genetics
  • Toxicology
  • Medicine(all)

Cite this

Griseofulvin. / De Carli, Luigi; Larizza, Lidia.

In: Mutation Research - Reviews in Genetic Toxicology, Vol. 195, No. 2, 1988, p. 91-126.

Research output: Contribution to journalArticle

De Carli, Luigi ; Larizza, Lidia. / Griseofulvin. In: Mutation Research - Reviews in Genetic Toxicology. 1988 ; Vol. 195, No. 2. pp. 91-126.
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