On the mechanism of lanthanide-induced liver toxicity.

Abstract

The intravenous injection of the lighter lanthanide ions Pr(III), Nd(III), and Sm(III) in doses of 35 mumoles/kg inhibits, and isoosmolar doses of the heavier lanthanide ions Gd(III), Dy(III), and Er(III) stimulate rat liver nuclear in vitro RNA synthesis catalyzed by RNA polymerase B 24 h after their application, while nuclear RNA synthesis, catalyzed by RNA polymerase A, was inhibited by the same isoosmolar doses of Pr(III), Nd(III) and not influenced by Sm(III), Gd(III), Dy(III), or Er(III). The effect of in vivo applied Pr(III) and Nd(III) on rat liver in vitro nuclear RNA synthesis shows a similar time and dose-dependent pattern. The decreased rat liver nuclear in vitro RNA synthesis 24 h after intravenous injection of Pr(III) as well as after Nd(III) was accompanied by a decreased nuclear in vitro 3H-acetate uptake by the chromatin-bound histone fractions, F 2a2, F 3, and F 2al. At the same time after the Pr(III) injection, the capacity and number of initiation sites of the rat liver nuclear template for homologous nuclear RNA polymerases, prepared from control rat liver nuclei, was lower than the corresponding control template. A decreased activity of endogenous free nuclear RNA polymerases, as determined with the aim of the synthetic poly(dA-dT) template 24 h after Pr(III), may further contribute to the decreased nuclear RNA synthesis. The results indicate a primary ionic size-correlated interference of lanthanides with the nuclear control mechanisms of RNA synthesis.