title: NAD(P)H: quinone oxidoreductase 1 deficiency conjoint with marginal vitamin C deficiency causes cigarette smoke induced myelodysplastic syndromes.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biotechnology and Dr. B. C. Guha Centre for Genetic Engineering and Biotechnology, Calcutta University College of Science, Kolkata, West Bengal, India.
authors.forename: Archita
authors.initials: A
authors.lastname: Das
authors.forename: Neekkan
authors.initials: N
authors.lastname: Dey
authors.forename: Arunava
authors.initials: A
authors.lastname: Ghosh
authors.forename: Tanusree
authors.initials: T
authors.lastname: Das
authors.forename: Indu B
authors.initials: IB
authors.lastname: Chatterjee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001205:Ascorbic Acid / Q000097:blood / Q000378:metabolism; D001206:Ascorbic Acid Deficiency / Q000503:physiopathology*; D001853:Bone Marrow / Q000378:metabolism; D005434:Flow Cytometry; D006168:Guinea Pigs; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D009190:Myelodysplastic Syndromes / Q000139:chemically induced* / Q000209:etiology*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000172:deficiency* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D017382:Reactive Oxygen Species; D014028:Tobacco Smoke Pollution; D016660:NAD(P)H Dehydrogenase (Quinone); D001205:Ascorbic Acid