NAD(P)H: Quinone Oxidoreductase 1 Deficiency Conjoint with Marginal Vitamin C Deficiency Causes Cigarette Smoke Induced Myelodysplastic Syndromes

Abstract

BackgroundThe 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.Methodology and Principal FindingsHere 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 and SignificanceCS 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.

Impact of tobacco usage on disease outcome in myelodysplastic syndromes

“…In an epidemiologic study by Korte et al, approximately 10–50% of smoking-induced total leukemia mortality and up to 60% of smoking-related AML mortality were suggested to be related to benzene exposure [23]. Animal models have demonstrated that the deficiency of cytosolic protein NAD(P)H: quinone oxidoreductase-1 (NQO1) may be associated with myeloid pathology, such as myeloid hyperplasia [24,25]. Additionally, NQO1 deficiency in conjunction with vitamin C deficiency may be a risk factor for developing MDS [25].…”

“…Animal models have demonstrated that the deficiency of cytosolic protein NAD(P)H: quinone oxidoreductase-1 (NQO1) may be associated with myeloid pathology, such as myeloid hyperplasia [24,25]. Additionally, NQO1 deficiency in conjunction with vitamin C deficiency may be a risk factor for developing MDS [25]. Recent analysis by Seastone et al [26] noted a greater number of molecular abnormalities in MDS patients, particularly related to histone modification highlighting potential tobacco-mediated molecular pathogenesis of MDS.…”

Brain Anatomy in Latino Farmworkers Exposed to Pesticides and Nicotine

“…The putamen findings were highly consistent with the present study. There has also been a report of actual increase in the volume of the putamen in smokers [81]. However, there have also been reports of decreased gray matter [34] and increased white matter [36] in the putamen of smokers.…”

Oxidases and reactive oxygen species during hematopoiesis: A focus on megakaryocytes

“…The progression to disease is also likely to be associated with a deficiency in the detoxification system, such as the NAD(P)H:quinine oxidoreductase (NQO1) deficiency in the HSCs (Rothman et al, 1997). An experimental model of cigarette smoke exposure in guinea pigs demonstrated the correlation between NQO1 deficiency, cigarette smoke exposure, and progression to MDS (Das et al, 2011). Moreover, as noted in our discussion of senescence and autophagy, mice deficient for Atg7 progress to a myeloproliferative disorder/MDS (Mortensen et al, 2011).…”