Induction of apoptosis and cell injury in kidney by active oxygen species produced by cytochrome P450

糖尿病和动脉硬化会引起肾脏和血管的细胞损伤。自由基被认为在这一途径中起重要作用，但其机制尚不清楚。细胞色素P450（P450）是一种产生活性氧的单加氧酶。活性氧引起DNA氧化和脂质过氧化，并诱导细胞凋亡。本研究探讨了P450s产生的活性氧在细胞凋亡和基因表达中的作用。苯巴比妥（PB）是p450的诱导剂，诱导活性氧和8-OHdG（一种DNA氧化标记物）的产生。PB还能诱导原癌基因、c-myc和细胞凋亡、DNA断裂。酮康唑，一种P450的抑制剂，抑制了所有这些途径。采用Hep 3B、肝癌细胞系和大鼠主动脉原代培养研究细胞缺血性损伤。氧张力降低（20%至1%）诱导超氧化物的产生，也诱导血红素加氧酶（在两个细胞中）和促红细胞生成素基因（在Hep 3B中）。作为NAD(P) h依赖性酶的抑制剂，DPIC降低了这些基因的表达。这些发现提示P450s产生的活性氧可诱导细胞凋亡和多种基因表达。P450在这一途径中发挥重要作用。

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.