Babich H, Zuckerbraun H L, Hirsch S T, Blau L
Department of Biology, Stern College for Women, Yeshiva University, New York, New York 10016, USA.
Pharmacol Toxicol. 1999 May;84(5):218-25. doi: 10.1111/j.1600-0773.1999.tb01486.x.
The cytotoxicity of the nitric oxide donor, S-nitroso-N-acetyl-penicillamine (SNAP), towards cultured human cells from oral tissue was evaluated. The toxicity of SNAP to Smulow-Glickman gingival epithelial cells was correlated with the liberation of nitric oxide, as N-acetyl-D,L-penicillamine, the SNAP metabolites, N-acetyl-D,L-penicillamine disulfide and nitrite, and preincubated (denitrosylated) SNAP did not affect viability. Comparing equimolar concentrations of various nitric oxide donors, cytotoxicity appeared to be inversely related to the relative stability (i.e., half-life) of the test compound; the sequence of cytotoxicity for a 4 hr exposure was S-nitrosoglutathione>>spermine NONOate> SNAP>DPTA NONOate>>DETA NONOate. Intracellular reduced glutathione (GSH) was lowered in S-G cells exposed to SNAP. Pretreatment of the cells with the GSH depleter, 1,3-bis-(chloroethyl)-1-nitrosourea (BCNU), enhanced the toxicity of SNAP Similar findings of enhanced sensitivity to SNAP were noted with gingival fibroblasts and periodontal ligament cells pretreated with BCNU. The toxicity of SNAP towards the gingival epithelial cells was decreased by cotreatment with the antioxidants, N-acetyl-L-cysteine, L-ascorbic acid, and (+)-catechin. Cells exposed to SNAP exhibited nuclear aberrations, including multilobed nuclei and multinucleation. SNAP-induced cell death was apparently by apoptosis, as noted by fluorescence microscopy and DNA agarose gel electrophoresis.
评估了一氧化氮供体S-亚硝基-N-乙酰青霉胺（SNAP）对培养的口腔组织人细胞的细胞毒性。SNAP对Smulow-Glickman牙龈上皮细胞的毒性与一氧化氮的释放相关，因为SNAP的代谢产物N-乙酰-D,L-青霉胺、N-乙酰-D,L-青霉胺二硫化物和亚硝酸盐以及预孵育（脱亚硝基化）的SNAP均不影响细胞活力。比较等摩尔浓度的各种一氧化氮供体，细胞毒性似乎与受试化合物的相对稳定性（即半衰期）呈负相关；4小时暴露的细胞毒性顺序为：S-亚硝基谷胱甘肽>>精胺亚硝酰基供体>SNAP>二丙三胺亚硝酰基供体>>二乙三胺亚硝酰基供体。暴露于SNAP的S-G细胞内的还原型谷胱甘肽（GSH）含量降低。用GSH消耗剂1,3-双（氯乙基）-1-亚硝基脲（BCNU）预处理细胞可增强SNAP的毒性。用BCNU预处理的牙龈成纤维细胞和牙周膜细胞对SNAP的敏感性增强也有类似发现。与抗氧化剂N-乙酰-L-半胱氨酸、L-抗坏血酸和（+）-儿茶素共同处理可降低SNAP对牙龈上皮细胞的毒性。暴露于SNAP的细胞表现出核异常，包括多叶核和多核。如荧光显微镜和DNA琼脂糖凝胶电泳所示，SNAP诱导的细胞死亡显然是通过凋亡实现的。
