Pharmacokinetics of Glutathione and Its Metabolites in Normal Subjects

To determine the loading and maintenance dosage of glutathione (GSH) for patients suffering from reactive oxygen species (ROS) injury such as acute paraquat intoxication, a kinetic study of reduced GSH was performed in synchrony with that of cysteine (Cys), cystine (Cys2), and methionine (Met). Human subject's porticipitation was voluntary. The effective dose of Cys, Cys2, and Met against ROS in fibroblast cells generated by paraquat was assessed using laser scanning confocal microscopy. Both Cys and Met suppressed ROS in a dose-dependent manner at concentrations of 1-1,000 micrometer; the concentration required to suppress ROS by 50% was 10 micrometer for Cys and 50 micrometer for Met. Using metabolite kinetics with the assumption that Cys and Met are the metabolites of GSH, expected concentrations of Cys and Met of above 20 and 50 micrometer were estimated when GSH was administered at 50 mg/kg body weights every 205.4 min for Cys and 427.4 min for Met.

Effects of Gangliosides on DNA Synthesis in U1242 MG Glioma Cells

Exogenously added gangliosides modulate the growth and differentiation of a variety of cells in vitro including human gliomas. GM1, Gdla and GTlb gangliosides inhibit both PDGF-stimulated and serum-stimulated DNA synthesis of Swiss 3T3 cells and U1242 MG cells in a dose responsive manner. The inhibitory effect is counteracted in a dose-responsive fashion by serum, and that ganglioside-induced inhibition is essentially abolished in 10% serum. Because of the potentially important role that gangliosides play in growth regulation of human gliomas, this phenomenon was studied in detail using the human glioma cell line U1242 MG. Low doses of serum stimulate DNA synthesis of U1242 MG cells which is inhibited in a dose-responsive fashion by ganglioside GMI. However, serum itself counteracts the inhibitory effect of ganglioside in a dose-responsive way. On the other hand GM,, Gdla and GTlb stimulate DNA synthesis in quiescent U1242 MG cells in both sparse and confluent conditions, indicating that ganglioside-stimulated DNA synthesis is dependent on the phase of cellular growth rather than celluar density. The growth stimulatory effect of the three gangliosides is more potent on quiescent, confluent cells than quiescent, sparse cells. Gangliosides stimulate radiolabeling of and 35% of nuclei with (3H) thymidine in quiescent, sparse and quiescent, confluent cells respectively. These results demonstrate that exogenously added gangliosides can have different effects on progression of human glioma cells, support of the bimodal behavior model of gangliosides. The effects are mainly related to cell cycle depending on the growth phase of the cells rather than the cell density.