We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Additive and synergistic effects of cyclosporine metabolites on glomerular mesangial cells.
- Authors
Radeke, Heinfried H.; Christians, Uwe; Bleck, Jörg S.; Sewing, Karl-F.; Resch, Klaus
- Abstract
Out of the 29 cyclosporin (Cs) metabolites defined so .far, 10 representative ones were isolated from bile of liver grafted patients, purified by HPLC, and their structure specified by FAB-MS and ¹H NMR. These were used to determine the growth inhibitory effects on Sprague Dawley rat glomerular mesangial cells (MC). Metabolite dilutions were added to cultured MC for 72 hours and [³H]-thymidine incorporation was measured. A 50% growth inhibition by single metabolites (M) on MC was achieved at the following concentrations (mg/liter): Cs: 1.25; M21: 6.0; M18: 9.0; M26: 10.5; M1: 10.8; M8: 10.8; M17: 12.5; M13: >20.0; M25: >25.0; M203–218: >50.0; H355: >50.0. The activity was correlated to the degree of metabolization as the group of six ‘active’ compounds included four primary metabolites (hydroxylated or demethylated derivatives of Cs: M21, M18, M1, M17), whereas the four ‘inactive’ compounds exclusively were secondary metabolites (demethylated, hydroxylated and/or oxidized primary metabolites: M13, M25, M203–218, H3.55). Combinations of active metabolites with or without Cs resulted m an additive antiproliferative effect. Although single metabolite activities are not relevant in vivo, already combinations of three (M1 + M17 + M18) or four metabolites (M17 + M18 + M21 + H355) resulted in a significant growth inhibition at concentrations of the participating metabolites measured in urine of fiver transplanted patients. Moreover, significant synergistic activities were determined with combinations including secondary metabolites. A final set of experiments discharged unspecific cytotoxic effects. The inhibition of MC [³H]-thymidine incorporation was completely reversible and moreover, direct mesangiolysis was excluded for both single and combined metabolite actions. Thus, considering rat MC proliferation as an initial kidney cell model system for subsequent, more detailed studies measuring functional parameters, we have demonstrated that activities of single metabolites are related to their chemical structure. More importantly, mimicking to some extent the patients' situation, combinations of metabolites at concentrations occurring in vivo reduced MC proliferation in culture in an at least an additive fashion, suggesting that side effects of Cs treatment might be attributed to combined Cs metabolite actions.
- Subjects
CYCLOSPORINE; IMMUNOSUPPRESSIVE agents; METABOLITES; BIOMOLECULES; KIDNEY glomerulus; LABORATORY rats
- Publication
Kidney International, 1991, Vol 39, Issue 6, p1255
- ISSN
0085-2538
- Publication type
Article
- DOI
10.1038/ki.1991.159