Use of human organ slices to evaluate the biotransformation and drug-induced side-effects of pharmaceuticals.
Human liver and kidney organ slices were used to investigate the biotransformation competence of the slices in combination with several markers of cell viability and function. The immunosuppressant cyclosporin A (CSA) is extensively metabolized in liver slices to the three known primary metabolites and many secondary metabolites. In kidney cortex slices the biotransformation of CSA is far more pronounced in humans than in rats. In human liver slices, levels of CYP3A, the proteins metabolizing CSA, are depressed about 25% by 1 and 10 mumol/L CSA within 24 h, indicating that high blood or tissue concentrations will inhibit CSA clearance. A clinical marker for liver damage is the release of cellular alpha-glutathione-S-transferases (alpha GST). In this study the alpha GST levels were used to assess donor organ quality, organ slice incubation conditions, and compound exposure. A marker for cell death in human cells is the solubilization and release of nuclear matrix proteins (Numa). Increases were apparent only after 48 h of culture. A side-effect of CSA is that it induces hypertension and perturbs the lipid profile of transplant recipients. A potential marker for lipid disturbances is levels of serum lipoprotein (a) (Lp(a)), which is synthesized in the liver and found only in humans, apes, and nonhuman primates. CSA increases Lp(a) levels in the human liver slice cultures about 2-fold. This study has demonstrated that the biotransformation capability of the organ slices contributes to the optimization of the in vitro system and to the evaluation of markers for drug induced side-effects or toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
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Sandoz Pharma Ltd., Basle, Switzerland.
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D017270:Lipoprotein(a) / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D009924:Organ Culture Techniques; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D011090:Polyenes / Q000494:pharmacology; D051381:Rats; D020123:Sirolimus; D018675:Toxicity Tests / Q000379:methods*
D017270:Lipoprotein(a); D009687:Nuclear Proteins; D011090:Polyenes; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D005982:Glutathione Transferase; D020123:Sirolimus