Differential association of T-2 and T-2 tetraol with mammalian cells

JL Middlebrook and DL Leatherman

Department of Toxinology, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland.

The interactions of T-2 and its metabolite T-2 tetraol (hereafter tetraol) with CHO (Chinese hamster ovary cells) and CHO ribosomes were studied. T-2 was about 300-fold more potent at inhibiting protein synthesis in CHO than was tetraol. Association of T-2 with CHO was highly specific and achieved a maximum at a concentration producing complete inhibition of protein synthesis. Association of tetraol with CHO was of low specificity, but the specific fraction did correlate with the dose-response curve for protein synthesis inhibition. Binding of both T-2 and tetraol to isolated CHO ribosomes was quantitatively similar and highly specific. With isolated ribosomes, each toxin competed effectively for the binding of the other. Using intact cells, tetraol competed for T-2 cell association, but not the converse. The kinetics at physiological temperature for total and specific T-2 cell association were much more rapid than those for tetraol. Furthermore, the rate of tetraol-cell association was indistinguishable from the rate for cellular uptake of tritiated water. At 0 degrees C, there was a substantial association of T-2 with cells, whereas none was observed with tetraol. The kinetics of dissociation of both toxins from CHO were similar. We conclude that T-2 rapidly crosses the cell membrane of cells and binds to the intracellular target, the ribosomes. In contrast, tetraol is taken up by the cell much more slowly, and many more toxin molecules are found in the cell than there are ribosomes. It would appear that the main physical property of the toxins that brings about these results is the relative hydrophobicities of the molecules.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 250, Issue 3, pp. 860-866, 09/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics

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