In vitro toxicity assessment of cyclosporin A and its analogs in a primary rat hepatocyte culture model

Toxicol Appl Pharmacol. 1988 Nov;96(2):212-21. doi: 10.1016/0041-008x(88)90081-6.


The cytotoxicity of cyclosporin A (CsA), a widely used immunosuppressant drug, was evaluated in primary cultures of rat hepatocytes. Furthermore, the concentration-dependent (10(-7) to 10(-5) M) cytotoxic effects of the cyclosporin analogs, CsG, CsH, CsF, and of a major metabolite of CsA, CsA/M17, were assessed in an attempt to classify the different cyclosporin analogs according to their in vitro hepatotoxic potential. All compounds invariably inhibited the net release of taurocholate (de novo synthesized from cholate added to the extracellular medium). This sensitive functional marker did not discriminate between the structural analogs. In addition, all compounds inhibited, to various extents, the biosynthesis and secretion of proteins without affecting the uptake rate of the nonmetabolizable amino acid, alpha-aminoisobutyric acid. These functional changes occurred in the absence of overt irreversible cell damage (no leakage of lactic dehydrogenase up to 10(-5) M cyclosporin during 17 hr of incubation). The relative toxic potential of the drug congeners (CsG greater than CsA greater than CsH = CsF = CsA/M17) correlated well with the degree of their accumulation in the hepatocytes during exposure to equimolar drug concentrations.

Publication types

  • Comparative Study

MeSH terms

  • Aminoisobutyric Acids / pharmacokinetics
  • Animals
  • Bile Acids and Salts / pharmacokinetics
  • Cells, Cultured
  • Cholic Acid
  • Cholic Acids / metabolism
  • Cyclosporins / metabolism
  • Cyclosporins / toxicity*
  • Dimethyl Sulfoxide / pharmacology
  • L-Lactate Dehydrogenase / metabolism
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Rats
  • Rats, Inbred Strains
  • Taurocholic Acid / metabolism


  • Aminoisobutyric Acids
  • Bile Acids and Salts
  • Cholic Acids
  • Cyclosporins
  • 2-aminoisobutyric acid
  • Taurocholic Acid
  • L-Lactate Dehydrogenase
  • Cholic Acid
  • Dimethyl Sulfoxide