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NAD(P)H: quinone oxidoreductase 1 deficiency conjoint with marginal vitamin C deficiency causes cigarette smoke induced myelodysplastic syndromes.

Das A, Dey N, Ghosh A, Das T, Chatterjee IB - PLoS ONE (2011)

Bottom Line: Apoptosis precedes MDS but disappears later with marked decrease in the p53 protein.However, after the onset of MDS vitamin C becomes ineffective.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biotechnology and Dr. B. C. Guha Centre for Genetic Engineering and Biotechnology, Calcutta University College of Science, Kolkata, West Bengal, India.

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.

Methodology and principal findings: 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 and significance: 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.

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Related in: MedlinePlus

NQO1 Activity of bone marrow cells of guinea pigs fed 0.5 mg or 15 mg vit C/day.(Panel A) AIR, exposed to air; DC, fed 3 mg DC/day; CS, exposed to CS; DC+CS, fed 3 mg DC/day and exposed to CS. * indicates significant difference (p<0.05) with respect to air exposed guinea pigs.(Panel B) NQO1 activity at different time periods of DC+CS group. * indicates significant difference (p<0.05) with respect to 0 day. Bars over the respective columns represent means ± SD (n = 6), Vit C means vitamin C.
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pone-0020590-g001: NQO1 Activity of bone marrow cells of guinea pigs fed 0.5 mg or 15 mg vit C/day.(Panel A) AIR, exposed to air; DC, fed 3 mg DC/day; CS, exposed to CS; DC+CS, fed 3 mg DC/day and exposed to CS. * indicates significant difference (p<0.05) with respect to air exposed guinea pigs.(Panel B) NQO1 activity at different time periods of DC+CS group. * indicates significant difference (p<0.05) with respect to 0 day. Bars over the respective columns represent means ± SD (n = 6), Vit C means vitamin C.

Mentions: NQO1 deficiency was produced by feeding an aqueous suspension of dicoumarol [3,3′-methylene-bis(4-hydroxycoumarine), Sigma, USA], an inhibitor of NQO1 [31]. Figure 1A shows that feeding dicoumarol (DC) at a dose of 3 mg/day for 21 days produces about 90% inhibition of NQO1 activity in the bone marrow of guinea pigs. The decrease in the NQO1 activity took place gradually up to 21 days of the experimental period (Figure 1B). Western blot analysis shows that there is no significant change in the NQO1 gene expression at the protein level (Figure S1).


NAD(P)H: quinone oxidoreductase 1 deficiency conjoint with marginal vitamin C deficiency causes cigarette smoke induced myelodysplastic syndromes.

Das A, Dey N, Ghosh A, Das T, Chatterjee IB - PLoS ONE (2011)

NQO1 Activity of bone marrow cells of guinea pigs fed 0.5 mg or 15 mg vit C/day.(Panel A) AIR, exposed to air; DC, fed 3 mg DC/day; CS, exposed to CS; DC+CS, fed 3 mg DC/day and exposed to CS. * indicates significant difference (p<0.05) with respect to air exposed guinea pigs.(Panel B) NQO1 activity at different time periods of DC+CS group. * indicates significant difference (p<0.05) with respect to 0 day. Bars over the respective columns represent means ± SD (n = 6), Vit C means vitamin C.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3105086&req=5

pone-0020590-g001: NQO1 Activity of bone marrow cells of guinea pigs fed 0.5 mg or 15 mg vit C/day.(Panel A) AIR, exposed to air; DC, fed 3 mg DC/day; CS, exposed to CS; DC+CS, fed 3 mg DC/day and exposed to CS. * indicates significant difference (p<0.05) with respect to air exposed guinea pigs.(Panel B) NQO1 activity at different time periods of DC+CS group. * indicates significant difference (p<0.05) with respect to 0 day. Bars over the respective columns represent means ± SD (n = 6), Vit C means vitamin C.
Mentions: NQO1 deficiency was produced by feeding an aqueous suspension of dicoumarol [3,3′-methylene-bis(4-hydroxycoumarine), Sigma, USA], an inhibitor of NQO1 [31]. Figure 1A shows that feeding dicoumarol (DC) at a dose of 3 mg/day for 21 days produces about 90% inhibition of NQO1 activity in the bone marrow of guinea pigs. The decrease in the NQO1 activity took place gradually up to 21 days of the experimental period (Figure 1B). Western blot analysis shows that there is no significant change in the NQO1 gene expression at the protein level (Figure S1).

Bottom Line: Apoptosis precedes MDS but disappears later with marked decrease in the p53 protein.However, after the onset of MDS vitamin C becomes ineffective.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biotechnology and Dr. B. C. Guha Centre for Genetic Engineering and Biotechnology, Calcutta University College of Science, Kolkata, West Bengal, India.

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.

Methodology and principal findings: 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 and significance: 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.

Show MeSH
Related in: MedlinePlus