Effects of therapeutic agents on cellular respiration as an indication of metabolic activity.
Animal experiments are indispensable in the investigation of the toxicity of drugs on cells, but may not be preferred for ethical reasons and sensitivity. As an alternative procedure, we investigated the susceptibility of cells to drugs using the effect on cellular respiration as an indicator of cell activity (toxicity). The primary cultures (cell lines) used in this study included human fetal myocardial cells, skeletal muscle cells, nerve cells, hypophyseal cells, epithelial cells of gastric mucosa, lymphocytes, hepatocytes, pancreatic (exocrine) cells, renal tubular epithelial cells and fetal adrenal cortex cells, which were obtained from the American Type Culture Collection (ATCC). The drugs used were diazepam, haloperidol and levomepromazine maleate (psychoactive drugs), cisplatin and doxorubicin hydrochloride (anticancer agents). The cells were used at a density of 2 x 10(6) cells/2 mL of growth medium and, to test the susceptibility, each drug was prepared at a concentration of 10 g/mL. Experiment results indicated that, even with the same drug, sensitivity was markedly different depending on the cell lines. Cardiac muscle cells showed the strongest respiratory inhibition by Serenace and were least inhibited by Hirnamin. The highest sensitivity to Cercine was noted for neurons, while gastric mucosa cells had almost no sensitivity. Sensitivity to Serenace, which was expected to have a strong nerve action, was higher in myocardial cells instead. In the present study, we suggested the possibility of studying individual differences in drug sensitivity through investigation of toxicity in each organ as opposed to toxicity in the individual. In addition, Serenace, which was developed as a neurotopic agent, showed a higher toxicity in cardiac muscle cells than in neurons. This finding appeared noteworthy, not only for forensic toxicology, but also for clinical practice and drug development.
Ishikawa
T
T
Department of Legal Medicine, Osaka City University Medical School, Asahi-machi 1-4-3, Abeno, Osaka 545-8585, Japan. takaki@med.osaka-cu.ac.jp
Zhu
B L
BL
Maeda
H
H
D002452:Cell Count; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003975:Diazepam / Q000494:pharmacology; D004566:Electrodes; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008660:Metabolism / Q000187:drug effects*; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010100:Oxygen / Q000032:analysis; D010101:Oxygen Consumption / Q000187:drug effects*
D006993:Hypnotics and Sedatives; D003975:Diazepam; D010100:Oxygen