Interaction of rifalazil with oxidant-generating systems of human polymorphonuclear neutrophils
Interaction of rifalazil with oxidant-generating systems of human polymorphonuclear neutrophils
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DOI：
10.1128/aac.49.12.5018-5023.2005
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发表时间：
2005-12-01
影响因子：
4.9
通讯作者：
Babin-Chevaye, C
中科院分区：
文献类型：
--
作者：
Labro, MT;Ollivier, V;Babin-Chevaye, C
众所周知，安沙霉素在体外和体内均表现出免疫抑制和抗炎特性。利福拉齐是一种新的安沙霉素衍生物，尚未在炎症背景下进行研究。特别是，没有关于利福拉齐可能干扰吞噬细胞产生氧化剂的数据。我们通过使用细胞和非细胞氧化剂生成系统，将利福拉齐的抗氧化特性与利福平（一种在这方面众所周知的药物）的抗氧化特性进行了比较。通过细胞色素 c 还原、光泽精放大化学发光 (Lu-ACL) 和 2',7'-二氯荧光素二乙酸酯 H-2 (DCFDA-H-2) 技术（细胞内氧化剂产生）来测量多形核中性粒细胞的氧化剂产生。利福拉齐以浓度依赖性方式损害O-2(-)产生，对于佛波醇肉豆蔻酸酯乙酸酯(PMA)和甲酰基-甲硫氨酰-亮氨酰-苯丙氨酸(fMLP)刺激，50%抑制浓度(IC50)(抑制50%反应的浓度)分别为5.4(孵育30和60分钟)和6.4(30分钟)mg/升。与已发表的利福平的 fMLP 样活性一致，利福平对 fMLP（IC50 为 5.6 mg/L）刺激的抑制作用显着大于对 PMA（IC50 为 58 mg/L）刺激的抑制作用。还观察到细胞内氧化剂产生的改变，其 IC50 值与细胞色素测定法获得的值相似。此外，如非细胞（次黄嘌呤-黄嘌呤氧化酶）系统所证明，利福拉齐和利福平（≥ 25 毫克/升）可清除 O-2(-)。 Lu-ACL 证明了这两种药物对光检测系统的干扰。体外证明的利福拉齐抗氧化作用的临床相关性，特别是其潜在的抗炎活性，需要进一步研究。
It is well acknowledged that ansamycins display immunosuppressive and anti-inflammatory properties in vitro and in vivo. Rifalazil, a new ansamycin derivative, has not been studied in the context of inflammation. In particular, there are no data on the possible interference of rifalazil with oxidant production by phagocytes. We have compared the antioxidant properties of rifalazil to those of rifampin, a drug well known in this context, by using cellular and acellular oxidant-generating systems. Oxidant production by polymorphonuclear neutrophils was measured in terms of cytochrome c reduction, lucigenin-amplified chemiluminescence (Lu-ACL), and the 2',7'-dichlorofluorescin diacetate H-2 (DCFDA-H-2) technique (intracellular oxidant production). Rifalazil impaired O-2(-) production in a concentration-dependent manner, with 50% inhibitory concentrations (IC50) (concentrations which inhibit 50% of the response) of 5.4 (30 and 60 min of incubation) and 6.4 (30 min) mg/liter, respectively, for phorbol myristate acetate (PMA) and formyl-methionyl-leucyl-phenylalanine (fMLP) stimulation. In agreement with the published fMLP-like activity of rifampin, the inhibitory effect of rifampin was significantly greater for fMLP (IC50 of 5.6 mg/liter) than for PMA (IC50 of 58 mg/liter) stimulation. Alteration of intracellular oxidant production was also observed with IC50 values similar to those obtained by the cytochrome assay. In addition, rifalazil and rifampin (>= 25 mg/liter) scavenged O-2(-), as demonstrated by the acellular (hypoxanthine-xanthine oxidase) system. Interference with light detection systems was evidenced for both drugs by Lu-ACL. The clinical relevance of the antioxidant effect of rifalazil demonstrated in vitro, in particular its potential anti-inflammatory activity, requires further investigation.