Free amino acids during chronic cyclosporine A toxicity in intact and partially nephrectomized rats.
The effects of 40 days of treatment with Cyclosporine A (CSA) on plasma and urine free amino acids were investigated in sham-operated (C) and partially nephrectomized (Pnx) female Fischer 344 rats. High Dose CSA (30 mg/kg/day ip) was associated with reduced weight gain, increased plasma urea nitrogen, and hypoproteinemia in C and Pnx animals. These animals also demonstrated increased plasma levels of alanine, markedly reduced levels of tryptophan, and an increase in urinary excretion of methylhistidines. C but not Pnx animals also showed a significant increase in plasma serine and a decrease in plasma taurine. CSA treatment of group C resulted in a progressive aminoaciduria involving substrates of the neutral and acidic renal amino acid transport systems; however, the renal excretion of taurine and beta-alanine by these animals was markedly reduced as compared to vehicle treated controls. High dose CSA exacerbated aminoaciduria in Pnx animals, but in this group, the excretion of beta amino acids was also increased. Our findings demonstrate that chronic CSA toxicity in rodents with normal renal function is characterized by increased muscle protein catabolism, significant reductions in plasma tryptophan, and an apparent decrease in whole body taurine pools. With the exception of the taurine abnormalities. CSA treatment had similar effects on Pnx animals; however, in this group, CSA-induced pathological changes were superimposed on the changes due to renal insufficiency per se. CSA toxicity as identified by the parameters investigated in this study was no more severe in Pnx animals with moderate chronic renal insufficiency than in controls with intact renal function.
Holmes
E W
EW
Department of Pathology, Loyola University Stritch School of Medicine, Maywood, Illinois 60153.
Kinzler
G J
GJ
Flanigan
R C
RC
Bermes
E W
EW
D000409:Alanine / Q000097:blood / Q000652:urine; D000596:Amino Acids / Q000097:blood / Q000378:metabolism* / Q000652:urine; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003524:Cyclosporins / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008762:Methylhistidines / Q000652:urine; D009392:Nephrectomy; D009584:Nitrogen / Q000652:urine; D051381:Rats; D011916:Rats, Inbred F344; D014364:Tryptophan / Q000097:blood / Q000652:urine
D000596:Amino Acids; D003524:Cyclosporins; D008762:Methylhistidines; D014364:Tryptophan; D009584:Nitrogen; D000409:Alanine