|Budget Amount *help
¥3,300,000 (Direct Cost : ¥3,300,000)
Fiscal Year 1999 : ¥600,000 (Direct Cost : ¥600,000)
Fiscal Year 1998 : ¥2,700,000 (Direct Cost : ¥2,700,000)
Diabetes and arteriosclerosis induce cell injury in a kidney and a blood vessel. Free radicals are thought to play an important role in such pathway but its mechanism isn't well understood. Cytochrome P450(P450) which is a monooxygenase produces active oxygen species. Active oxygen species cause DNA oxidation and lipid peroxidation and also induce apoptosis. In this study, a role of active oxygen species produced by P450s in apoptosis and gene expression was investigated. Phenobarbital (PB), an inducer of P450s, induced production of active oxygen, and 8-OHdG (a DNA oxidation marker). PB also induced proto-oncogene, c-myc and apoptosis, DNA fragmentation. Ketoconazole, an inhibitor of P450, inhibited all these pathways. Furthermore, Hep 3B, hepatoma cell line, and primary culture of rat aorta were used to investigate ischemic injury of cell. Reduction of oxygen tension (20% to 1%) induced production of superoxide and also induced heme oxygenase (in both cells) and erythropoietin genes (in Hep 3B). DPIC, an inhibitor of NAD(P)H-dependent enzymes, decreased expression of these genes.
These findings suggest that active oxygen species produced by P450s induced apotosis and several gene expression. P450 has an important role in this pathway.