Tissue specificity of translation inhibition in Sprague-Dawley rats following in vivo cyclosporin A.
We have shown that following the in vivo administration of cyclosporin A (CsA) to either male or female Sprague-Dawley rats, there is a time- and dose-dependent inhibition of translation elongation in renal microsomes. Experiments reported in this paper explore the tissue specificity of translation inhibition. Following 6 days of oral 50 mg/kg/day CsA or control vehicle, animals were sacrificed and renal, hepatic and cardiac microsomal and cytoplasmic fractions prepared for "run-off" translation assays. These assays demonstrated that in vivo CsA resulted in a reduction in renal microsomal 3H-L-leucine incorporation to 25% of control values, a reduction of cardiac microsomal incorporation to 60% of controls and a stimulation of hepatic microsomal incorporation to 140% of controls. Cross-over experiments involving the addition of renal cytoplasmic fractions from CsA-treated animals to renal microsomal fractions from control-vehicle-treated animals depressed 3H-L-leucine incorporation to approximately 50% of control values. When the renal cytoplasmic fraction from CsA-treated animals was added to renal, hepatic or cardiac microsomal fractions from control-vehicle-treated animals, 3H-L-leucine incorporation values were consistently reduced to approximately 50% of controls. We have reported that translation elongation is inhibited by renal cytoplasm from CsA-treated rats in the presence of control renal cytoplasm. These data suggest that inhibition arises from the presence of an inhibitor rather than from a deficiency in elongation factors. The data reported in this paper demonstrate that microsomal fractions from various tissues have equal sensitivity to CsA-mediated renal cytoplasmic translation inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
Buss
W C
WC
Department of Pharmacology, University of New Mexico School of Medicine, Albuquerque 87131.
Stepanek
J
J
D000818:Animals; D016572:Cyclosporine / Q000633:toxicity*; D005260:Female; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009928:Organ Specificity; D014176:Protein Biosynthesis / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016572:Cyclosporine