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

细胞色素P450产生的活性氧诱导肾脏细胞凋亡和细胞损伤

• 批准号: 10670094
• 负责人: IMOKA Susumu
• 金额: $ 2.11万
• 依托单位: Osaka City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670094/
• 关键词: cytochrome P450; super oxide; hypoxia; kidney; blood vessel; シトクロム P450; Hypoxia; アポトーシス

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.

糖尿病和动脉硬化会引起肾脏和血管的细胞损伤。自由基被认为在这种途径中发挥着重要作用，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。活性氧会导致 DNA 氧化和脂质过氧化，并诱导细胞凋亡。在本研究中，研究了 P450 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，可诱导活性氧和 8-OHdG（DNA 氧化标记）的产生。 PB还诱导原癌基因、c-myc和细胞凋亡、DNA断裂。酮康唑是 P450 的抑制剂，可抑制所有这些途径。此外，使用Hep 3B、肝癌细胞系和大鼠主动脉原代培养物来研究细胞的缺血性损伤。氧张力的降低（20% 至 1%）诱导超氧化物的产生，还诱导血红素加氧酶（在两种细胞中）和促红细胞生成素基因（在 Hep 3B 中）。 DPIC 是 NAD(P)H 依赖性酶的抑制剂，可降低这些基因的表达。这些发现表明 P450 产生的活性氧诱导细胞凋亡和多种基因表达。 P450 在此途径中发挥重要作用。

项目成果

M.Nakamura, S.Imaoka, F.Amano, and Y.Funae: "P450 isoforms in a murine macrophage cell line, RAW264.7, and changes in the levels of P450 isoforms by activation with LPS and INF-γ"Biochem.Biophys.Acta. 1385. 101-106 (1998)

M.Nakamura、S.Imaoka、F.Amano 和 Y.Funae：“小鼠巨噬细胞系 RAW264.7 中的 P450 异构体，以及 LPS 和 INF-γ 激活导致的 P450 异构体水平的变化”Biochem。生物物理学报。1385。101-106（1998）

T. Ichihara et al.: "Inhibition of liver flutathione S-transferase placental form-positive foci development in the rat hepatocarcinogenesis by Porphyra tenera (Asakusa-nori)"Cancer Lett.. 141. 211-218 (1999)

T. Ichihara 等人：“淡紫菜（浅草紫菜）对大鼠肝癌发生中肝氟他硫酮 S-转移酶胎盘形式阳性病灶发育的抑制”Cancer Lett.. 141. 211-218 (1999)

M. Nakamura, S. Imaoka et al.: "P450 isoforms in a murine macrophage cell line, RAW264.7, and changes in the levels of P450 isoforms by activation with LPS and INF-γ"Biochem. Biophys. Acta. 1385. 101-106 (1998)

M. Nakamura, S. Imaoka 等人：“鼠巨噬细胞系 RAW264.7 中的 P450 异构体，以及 LPS 和 INF-γ 激活导致的 P450 异构体水平的变化”Biochem 1385。 101-106（1998）

S.Takemura, Y.Minamiyama, S.Imaoka, Y.Funae, K.Hirohashi, M.Inoue, and H.Kinoshita: "Hepatic cytochrome P450 is directly inactivated by nitric oxide, not by inflammatory cytokines, in the early phase of endotoxemia"J.Hepatol. 30. 1035-1044 (1999)

S.Takemura、Y.Minamiyama、S.Imaoka、Y.Funae、K.Hirohashi、M.Inoue 和 H.Kinoshita：“在早期阶段，肝细胞色素 P450 直接被一氧化氮而不是炎症细胞因子灭活。

M. Kitano et al.: "Presence of a threshold for promoting effects of phenobarbital on diethylnitrosamine-induced hepatic foci in the rat"Carcinogenesis. 19. 1475-1480 (1998)

M. Kitano 等人：“苯巴比妥对二乙基亚硝胺诱导的大鼠肝病灶的促进作用的阈值的存在”致癌作用。