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Old 07-18-2011
yasirsattar75's Avatar
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Drug how hydroxyurea increase Hbf synthesis?

hi can anyone explain this mechanism that how hydroxyurea increases Hbf synthesis ? i only know that hydroxyurea inhibits enzyme ribonucleotide reducatas in pyrimidine synthesis .... what the full mechanism how its increases Hbf ??????
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Old 07-18-2011
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Good question, it is not HY nor questionable (hopefully), just as interest,

Human erythroid progenitor cells contain eNOS mRNA and protein and demonstrate eNOS activity. We observed a fall in eNOS mRNA and protein levels as well as its activity during erythroid differentiation, concomitantly with the elevation of hemoglobin levels. We found a continuous decrease in cAMP high levels in contrast to steady low levels of cGMP during erythroid differentiation. So, the eNOS protein level, as well as cAMP levels, continuously decline during erythroid differentiation. Their activity and presence is parallel to gamma-globin gene expression, which also declines during erythroid differentiation. Hydroxyurea, a drug which stimulates gamma-globin gene expression, increased steady intracellular cGMP levels as well as cAMP levels in human erythroid progenitor cells, whereas the NO donor increased intracellular cGMP levels but reduced cAMP levels. The cAMP signal is adjusted by cAMP degradation determined by phosphodiesterases 3 (PDE3) in erythroid cells, where the PDE3 is inhibited due to activation of sGC.21
Using purified sGC we demonstrated that hydroxyurea could directly interact with deoxy-heme of sGC, generating the iron-nitrosyl complex, and consequently activating cGMP production. These results are all consistent with an NO-dependent sGC mechanism for the elevation of HbF in erythroid progenitor cells. (Hydroxyurea nitrosylates and activates soluble guanylyl cyclase in human erythroid cells, Blood, Feb, 2008)

So, briefly, hydroxiurea keeps erythroid line cells "young"-> production of fetal Hb...

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