Mebendazol Benzimidazois. Histórico dos efeitos no citoesqueleto - 7 trabalhos

[The embryotoxic and antimitotic properties of a series of benzimidazoles].

[Article in French] Therapie. 1976 Jul-Aug;31(4):505-15. Delatour P, Richard Y. PMID:1034351

Interaction of anthelmintic benzimidazoles and benzimidazole derivatives with bovine brain tubulin.

Friedman PA, Platzer EG.

Biochim Biophys Acta. 1978 Dec 18;544(3):605-14.

Abstract

The binding and inhibitory properties of 11 benzimidazoles for bovine brain tubulin were investigated. The effects of the benzimidazoles on the initial rates of microtubule polymerization were determined by a turbidimetric assay. The median inhibitory concentrations (I50) for nocodazole, oxibendazole, parbendazole, mebendazole and fenbendazole ranged from 1.97 . 10(-6) to 6.32 . 10(-6) M. Benomyl, cambendazole and carbendazim had I50 values from 5.83 . 10(-5) to 9.01 .10(-5) M. Thiabendazole had an I50 value of 5.49 . 10(-4) M. Inhibitor constants (Ki) were determined by the colchicine binding assay. Oxibendazole, fenbendazole, and cambendazole had Ki values of 3.20 . 10(-5), 1.73 . 10(-5) and 1.10 . 10(-4) M, respectively. Oxibendazole and fenbendazole were competitive inhibitors of colchicine. In contrast, cambendazole was a noncompetitive inhibitor of colchicine. The ability of these benzimidazoles to inhibit microtubule polymerization and the mode of action for the anthelmintic benzimidazoles is discussed.

PMID:728472

The interaction of benzimidazole carbamates with mammalian microtobule protein.

Ireland CM, Gull K, Gutteridge WE, Pogson CI. Biochem Pharmacol. 1979 Sep 1;28(17):2680-2. PMID:518680

Inhibition of tubulin polymerization by mebendazole.

Laclette JP, Guerra G, Zetina C. Biochem Biophys Res Commun. 1980 Jan 29;92(2):417-23. PMID:7356473

Intestinal tubulin as possible target for the chemotherapeutic action of mebendazole in parasitic nematodes.

Köhler P, Bachmann R.

Mol Biochem Parasitol. 1981 Dec 31;4(5-6):325-36.

Abstract

In vitro incubation of the parasitic nematode Ascaris suum in the presence of 10 microM mebendazole (MBZ) resulted in a complete loss of colchicine binding ability of extracts obtained from the parasite's intestine. Biochemical evidence supported the identification of the colchicine binding receptor in A. suum intestinal extracts as tubulin. This protein was partially purified and found to comprise approximately 0.8% of the soluble intestinal protein. MBZ inhibited colchicine binding to the partially purified tubulin in a competitive manner, the inhibition constant being 4.22 X 10(-6) M. Colchicine binding to porcine brain tubulin was also competitively inhibited by MBZ, exhibiting an inhibition constant of 8.0 X 10(-6) M. [3H]Colchicine binding studies revealed an apparent association constant of A. suum tubulin of 5.88 X 10(4) M(-1). Similar experiments employing [3H]MBZ showed that the extent of MBZ binding to the tubulin up to 10(-5) M was linearly dependent on MBZ concentration. Due to solubility problems the precise association constant for MBZ could not be determined but is apparently less than 10(5) M(-1). In view of the small difference in drug binding abilities between nematode intestinal and mammalian brain tubulin it still remains unclear whether the selective toxicity of MBZ can be solely explained by its interference with the parasite's microtubular system. Further studies reported in this paper suggest that a differential pharmacokinetic behaviour of MBZ between parasite and host may be the essential basis for the difference in drug susceptibility between both biological systems.

PMID:7335116

Binding of [3H]benzimidazole carbamates to mammalian brain tubulin and the mechanism of selective toxicity of the benzimidazole anthelmintics.

Russell GJ, Gill JH, Lacey E.

Biochem Pharmacol. 1992 Mar 3;43(5):1095-100.

Source

Department of Veterinary Pathology, University of Sydney, N.S.W., Australia.

Abstract

The binding of tritiated benzimidazole carbamates ([3H]BZCs) to mammalian brain tubulin was examined to investigate the kinetics of the BZC-tubulin interaction and to establish the mechanism of the selective toxicity of the BZC based anthelmintics. [3H]BZC binding to tubulin was markedly greater at 4 degrees than at 37 degrees for all ligands. The association constant (Ka) and maximum amount of [3H]BZC bound (Bmax) were temperature dependent for [3H]mebendazole ([3H]MBZ), [3H]oxibendazole ([3H]-OBZ) and [3H]oxfendazole ([3H]OFZ). The Ka and Bmax values obtained for [3H]MBZ, [3H]OBZ and [3H]OFZ, and the comparatively weak binding of [3H]carbendazim, reflected the known in vitro potency of these compounds as microtubule inhibitors. Dissociation of the [3H]MBZ-tubulin complex was also temperature dependent, the first order dissociation rate constant being reduced by two orders of magnitude at 4 degrees compared with that observed for 37 degrees. These results indicate that the binding of BZCs to mammalian brain tubulin is temperature dependent and suggest that temperature induced conformational changes in the tubulin dimer influence the ability of the BZCs to form a stable BZC-tubulin complex. The temperature dependence of BZC binding and the affinity of the BZCs for mammalian tubulin are therefore unlike the BZC-tubulin interaction observed for parasitic nematodes, where optimum BZC binding occurs at 37 degrees and results in the formation of a pseudo-irreversible complex.

PMID:1554382

The role of the cytoskeletal protein, tubulin, in the mode of action and mechanism of drug resistance to benzimidazoles.

Lacey E.

Int J Parasitol. 1988 Nov;18(7):885-936.

Erratum in

 Int J Parasitol 1989 May;19(3):359.

PMID:3066771