Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.11.1.7 (peroxidase)
 65,474 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vesnarinone is an important new drug that significantly decreases mortality rates in severe congestive heart failure; however, its use is associated with a relatively high incidence (approximately 1%) of agranulocytosis. The authors studied its metabolism by activated neutrophils, the target for this toxicity, and evidence pointed to a pathway that involved a reactive iminium ion. Hydrolysis of the iminium ion led to a reactive quinone imine. The same pathway was observed with a combination of myeloperoxidase/hydrogen peroxide/chloride, the major oxidizing system of neutrophils, or hypochlorous acid, which is generated by this system. Activation of the neutrophils could be achieved by phorbol ester or by influenza vaccine and there is evidence to suggest that the administration of influenza vaccine during vesnarinone therapy may increase the risk of agranulocytosis. Incubation of radiolabeled vesnarinone with activated neutrophils led to covalent binding of almost 5% of the drug to the cells. Both the iminium ion and quinone imine generated by hypochlorous acid could be trapped with glutathione. It was proposed that these reactive metabolites, generated by neutrophils or neutrophil precursors in the bone marrow, may be responsible for the vesnarinone-induced agranulocytosis. Factors such as infection or vaccination that activate neutrophils may increase the risk of agranulocytosis.
 ...
PMID:Metabolism of vesnarinone by activated neutrophils: implications for vesnarinone-induced agranulocytosis. 793 98

It has been reported that vesnarinone, a new inotropic agent used in the treatment of cardiac failure, causes agranulocytosis as a side effect. To study the mechanisms by which this complication occurs, vesnarinone was introduced into a coculture system of HL60 and bone marrow (BM) stromal cells, in which HL60 cells were able to differentiate into mature granulocytes with no inducible exogenous factors added to the culture. When HL60 cells were cocultured with the human BM-derived stromal cell line LP101, HL60 cells were induced to differentiate into mature granulocytes, and expression of the mature granulocyte-macrophage surface antigen, CD11b was increased. Conditioned medium (CM) obtained from LP101 cells also showed the capacity to induce the maturation of HL60 cells, in a dose- and time-dependent manner. The differentiation of HL60 cells induced by CM was also determined by morphological analysis, expression of myeloperoxidase, and a nitroblue tetrazolium (NBT) reduction test. When HL60 cells were cocultured with LP101 in the presence of vesnarinone, the CD11b expression was greatly suppressed. CM obtained from vesnarinone-treated LP101 (ves-CM) lost the capacity to induce the differentiation of HL60 cells, at a concentration of 1 microg/mL of vesnarinone. Vesnarinone itself did not affect the proliferation of HL60 cells. Furthermore, the addition of vesnarinone or ves-CM to HL60 cultures incubated with CM did not alter the induction of CD11b expression, suggesting that vesnarinone has no effect on HL60 cells, but that it inhibits stromal cells from producing soluble factor(s) required for the differentiation of HL60 cells to mature granulocytes. All these findings indicate that vesnarinone causes the hematopoietic disorder agranulocytosis, via impairment of stromal function.
 ...
PMID:Effects of vesnarinone on the bone marrow stromal cell-dependent proliferation and differentiation of HL60 cells in vitro. 919 29