Yuann J M, Liu K J, Hamilton J W, Wetterhahn K E
Department of Chemistry, Dartmouth College, Department of Radiology and Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755-3564, USA.
Carcinogenesis. 1999 Jul;20(7):1267-75. doi: 10.1093/carcin/20.7.1267.
Several previous in vitro studies have indicated that ascorbate and glutathione are the major reductants of Cr(VI) in cells. In order to evaluate the in vivo effects of ascorbate and glutathione on Cr(VI)-induced carcinogenesis, Cr uptake and the formation of Cr(V), Cr-DNA adducts and 8-hydroxy-2'-deoxyguanosine (8-OH-dG) were measured in the liver and kidney of Osteogenic Disorder Shionogi (ODS) rats that lack the ability to synthesize ascorbate. Despite a 10-fold difference in tissue ascorbate levels among different dietary ascorbate groups, the Cr(V) signal intensity, Cr uptake and total Cr-DNA binding were not affected in either organ. Treatment of ODS rats with Cr(VI) (10 mg/kg) had no substantial effect on the levels of ascorbate and glutathione in these tissues. The levels of Cr(V) and Cr-DNA binding were approximately 2-fold higher in the liver than in the kidney, although the levels of total Cr uptake were similar in both tissues. Cr uptake levels were significantly lower in the liver and kidney of ODS rats treated with high levels of ascorbate and a high dose of Cr(VI) (40 mg/kg), suggesting a detoxifying role played by plasma ascorbate. Similarly, modulation of glutathione levels by N-acetyl-L-cysteine, L-buthionine-S, R-sulfoximine or phorone in these animals by up to 2-fold had little or no consistent effect on Cr uptake, Cr-DNA binding, Cr(V) levels or 8-OH-dG formation in either organ. One possible explanation is that reduction of ascorbate and glutathione concentration to <10 and 50%, respectively, of normal in these two organs still provides threshold levels of these two reductants that are in excess of what is needed for significant reductive activation of Cr(VI). Alternatively, it is possible that ascorbate and glutathione do not play a major role in the formation of Cr(V), Cr-DNA binding or 8-OH-dG and that other cellular reductants, such as cysteine or other amino acids, might be more important reductants of Cr(VI) in vivo.
此前的多项体外研究表明，抗坏血酸和谷胱甘肽是细胞中六价铬的主要还原剂。为了评估抗坏血酸和谷胱甘肽对六价铬诱导的致癌作用的体内影响，在缺乏合成抗坏血酸能力的成骨障碍史氏（ODS）大鼠的肝脏和肾脏中，测量了铬的摄取以及五价铬、铬 - DNA加合物和8 - 羟基 - 2'-脱氧鸟苷（8 - OH - dG）的形成。尽管不同饮食抗坏血酸组之间组织抗坏血酸水平存在10倍差异，但任一器官中的五价铬信号强度、铬摄取和总铬 - DNA结合均未受到影响。用六价铬（10 mg/kg）处理ODS大鼠对这些组织中的抗坏血酸和谷胱甘肽水平没有实质性影响。肝脏中的五价铬水平和铬 - DNA结合比肾脏中大约高2倍，尽管两个组织中的总铬摄取水平相似。用高剂量抗坏血酸和高剂量六价铬（40 mg/kg）处理的ODS大鼠的肝脏和肾脏中的铬摄取水平显著降低，表明血浆抗坏血酸起到了解毒作用。同样，通过N - 乙酰 - L - 半胱氨酸、L - 丁硫氨酸 - S，R - 亚砜亚胺或佛波酮将这些动物体内的谷胱甘肽水平调节高达2倍，对任一器官中的铬摄取、铬 - DNA结合、五价铬水平或8 - OH - dG形成几乎没有一致的影响。一种可能的解释是，将这两个器官中的抗坏血酸和谷胱甘肽浓度分别降低至正常水平的<10%和50%，仍然提供了这两种还原剂的阈值水平，超过了六价铬显著还原活化所需的水平。或者，有可能抗坏血酸和谷胱甘肽在五价铬、铬 - DNA结合或8 - OH - dG的形成中不起主要作用，而其他细胞还原剂，如半胱氨酸或其他氨基酸，可能是体内六价铬更重要的还原剂。
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