The dose-dependent inhibition of rat renal translation elongation seen after in vivo cyclosporin A is not caused by cyclosporin metabolites.
Cyclosporin A (CsA) given to Sprague-Dawley rats in vivo produced a tissue-specific, dose-dependent inhibition of translation elongation in renal microsomes. CsA at an oral dose of 50 mg/kg/day for 6 days reduced renal microsomal translation by 70.5%. Renal cytoplasm from rats treated in vivo with CsA inhibited translation by 55% when added to renal microsomes isolated from tissues of control animals. In contrast, CsA added to renal microsomes in vitro did not inhibit translation. Renal cytoplasm from CsA-treated rats containing translation inhibitory factor was found by HPLC to contain CsA and CsA metabolites M1 and M17. CsA metabolites M1, M17, M18 and M21 were isolated from human bile and tested in vitro for translation elongation inhibitory activity in renal microsomes. CsA, M18 and M21 did not inhibit translation elongation at concentrations of up to 2500 ng/ml. M17 inhibited translation elongation, but only by 8.4% at the highest concentration tested (2500 ng/ml), a level 20-fold higher than that measured in renal cytoplasm (125 ng/ml). M1 produced a concentration-dependent inhibition of translation elongation, beginning at 500 ng/ml, or approximately 2-fold higher than that found in renal cytoplasm (260 ng/ml). M1 at 2500 ng/ml or approximately 10-fold higher than the concentration measured in renal cytoplasm, inhibited translation elongation by 23.8%, only 1/3 that observed upon addition of renal cytoplasm containing translation inhibitory factor. We conclude from these findings that the dose-dependent inhibition of renal translation elongation following in vivo CsA cannot be explained by the renal formation or uptake of known CsA metabolites.
Buss
W C
WC
Department of Pharmacology, University of New Mexico School of Medicine, Albuquerque 87131, USA.
Bowers
L D
LD
D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000737:chemistry / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007553:Isotope Labeling; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014316:Tritium / Q000378:metabolism
D014316:Tritium; D016572:Cyclosporine; D007930:Leucine