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 biotr ansformation competence of the slices in combination with several mark ers 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 s lices the biotransformation of CSA is far more pronounced in humans th an in rats. In human liver slices, levels of CYP3A, the proteins metab olizing CSA, are depressed about 25% by 1 and 10 mu mol/L CSA within 2 4 h, indicating that high blood or tissue concentrations will inhibit CSA clearance. A clinical marker for liver damage is the release of ce llular 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 pr oteins (Numa). Increases were apparent only after 48 h of culture. A s ide-effect of CSA is that it induces hypertension and perturbs the lip id profile of transplant recipients. A potential marker for lipid dist urbances is levels of serum lipoprotein (a) (Lp(a)), which is synthesi zed 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 capabili ty 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. Assays were identified that could be used clinically to monitor CSA-induced organ damage or rejection (alpha GST), hypertensio n (Lp(a)), and toxicity (Numa).