Molecular Pharmacology, Vol 20, 35-42, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

Binding Properties of Zearalenone Mycotoxins to Hepatic Estrogen Receptors

¹ Laboratory of Organ Function and Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

This study investigates binding characteristics of three derivatives of the estrogenic mycotoxin zearalenone by components of liver cytosol. Studies show that cytosol from male and female rats contain similar amounts of specific estrogen receptors which sediment in the 8-9 S region of 5-20% sucrose gradients. In addition, male liver cytosol contains a second class of "nonreceptor" estrogen-binding sites sedimenting in the 4-5 S region of sucrose gradients. Sedimentation analyses show that each of the mycotoxin derivatives (P-1496, P-1502, and P-1560) behave in an analogous manner to the synthetic estrogen, diethylstilbestrol, in that they compete effectively for 8 S receptor sites, whereas they bind poorly to 4 S nonreceptor sites. The binding affinities of the derivatives for receptor sites were determined from competition studies at 4° by using partially purified receptors and a range of concentrations of the competing ligands. During a short (90-min) incubation period, the relative binding affinities of P-1496, P-1502, and P-1560 for receptor sites were 30, 17, and 12%, respectively, of that exhibited by 17-estradiol. The relative binding affinity of 17-estradiol and P-1496 did not change as a function of time at 4°. However, the relative binding affinities of P-1502 and P-1560 decreased to 6.8 and 4.2%, respectively, during an extended incubation period at 4°. The binding affinity of each derivative was similar towards partially purified liver and uterine receptors during the extended incubation period. Dissociation rate constants of 17-estradiol, P-1496, and P-1560 were obtained indirectly by measuring the rate of exchange of the unlabeled ligand with [³H]estradiol at 25°. The dissociation rate constants were 3.0 x 10^-3 min^-1, 5.6 x 10^-3 min^-1, and 0.14 min^-1 for 17-estradiol, P-1496, and P-1560, respectively. These studies show that the mycotoxin derivatives have the potential for modulating liver function through interaction with specific estrogen receptors. The true estrogen potential of the derivatives may depend upon the formation of a stable slowly dissociating ligand-receptor complex.

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