Department of Biotechnology and Dr. B. C. Guha Centre for Genetic Engineering and Biotechnology, Calcutta University College of Science, Kolkata, West Bengal, India.
PLoS One. 2011;6(5):e20590. doi: 10.1371/journal.pone.0020590. Epub 2011 May 31.
The etiology of myelodysplastic syndromes (MDS) is largely unknown. Exposure to cigarette smoke (CS) is reported to be associated with MDS risk. There is inconsistent evidence that deficiency of NAD(P)H-quinone: oxidoreductase 1 (NQO1) increases the risk of MDS. Earlier we had shown that CS induces toxicity only in marginal vitamin C-deficient guinea pigs but not in vitamin C-sufficient ones. We therefore considered that NQO1 deficiency along with marginal vitamin C deficiency might produce MDS in CS-exposed guinea pigs.
Here we show that CS exposure for 21 days produces MDS in guinea pigs having deficiency of NQO1 (fed 3 mg dicoumarol/day) conjoint with marginal vitamin C deficiency (fed 0.5 mg vitamin C/day). As evidenced by morphology, histology and cytogenetics, MDS produced in the guinea pigs falls in the category of refractory cytopenia with unilineage dysplasia (RCUD): refractory anemia; refractory thrombocytopenia that is associated with ring sideroblasts, micromegakaryocytes, myeloid hyperplasia and aneuploidy. MDS is accompanied by increased CD34(+) cells and oxidative stress as shown by the formation of protein carbonyls and 8-oxodeoxyguanosine. Apoptosis precedes MDS but disappears later with marked decrease in the p53 protein. MDS produced in the guinea pigs are irreversible. MDS and all the aforesaid pathophysiological events do not occur in vitamin C-sufficient guinea pigs. However, after the onset of MDS vitamin C becomes ineffective.
CS exposure causes MDS in guinea pigs having deficiency of NQO1 conjoint with marginal vitamin C deficiency. The syndromes are not produced in singular deficiency of NQO1 or marginal vitamin C deficiency. Our results suggest that human smokers having NQO1 deficiency combined with marginal vitamin C deficiency are likely to be at high risk for developing MDS and that intake of a moderately large dose of vitamin C would prevent MDS.
骨髓增生异常综合征（MDS）的病因在很大程度上尚不清楚。据报道，吸烟会增加 MDS 的风险。有证据表明，烟酰胺腺嘌呤二核苷酸磷酸（NAD(P)H）醌氧化还原酶 1（NQO1）缺乏会增加 MDS 的风险，但证据并不一致。我们之前的研究表明，香烟烟雾仅在边缘性维生素 C 缺乏的豚鼠中引起毒性，而在维生素 C 充足的豚鼠中则不会。因此，我们认为 NQO1 缺乏加上边缘性维生素 C 缺乏可能会在暴露于香烟烟雾的豚鼠中产生 MDS。
在这里，我们展示了 CS 暴露 21 天会导致 NQO1 缺乏（每天喂食 3mg 双香豆素）并伴有边缘性维生素 C 缺乏（每天喂食 0.5mg 维生素 C）的豚鼠发生 MDS。从形态学、组织学和细胞遗传学上看，豚鼠中产生的 MDS 属于难治性细胞减少症伴单系发育不良（RCUD）：难治性贫血；难治性血小板减少症，伴有环形铁幼粒细胞、微小巨核细胞、骨髓增生和非整倍体。MDS 伴随着 CD34+细胞的增加和氧化应激，表现为蛋白质羰基和 8-氧脱氧鸟苷的形成。凋亡先于 MDS 发生，但随着 p53 蛋白的显著减少，凋亡后来消失。豚鼠中产生的 MDS 是不可逆的。维生素 C 充足的豚鼠不会发生 MDS 和上述所有病理生理事件。然而，在 MDS 发生后，维生素 C 变得无效。
CS 暴露会导致 NQO1 缺乏并伴有边缘性维生素 C 缺乏的豚鼠发生 MDS。在 NQO1 或边缘性维生素 C 缺乏的单一情况下，不会产生综合征。我们的结果表明，同时存在 NQO1 缺乏和边缘性维生素 C 缺乏的人类吸烟者可能面临 MDS 发展的高风险，而摄入适量大剂量的维生素 C 可以预防 MDS。
