Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002874 (aplastic anemia)
 5,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been suggested that in the chloramphenicol-induced aplastic anemia nitrosochloramphenicol may be involved as a toxic intermediate. We found that aminochloramphenicol, which reportedly is formed from chloramphenicol by intestinal bacteria, is N-oxygenated by liver microsomes of untreated rats with apparent Km = 0.4 mM and Vmax = 0.28 nmole/min/mg protein. These values are in close agreement with those reported for aniline N-oxygenation. Reductive reactions, however, eliminate the N-oxygenation products at markedly higher rates. As judged from hemoglobin-free single-pass liver perfusion experiments, N-hydroxy-chloramphenicol is reduced at rates faster than 300 nmole/min/g liver wet, and nitrosochloramphenicol is eliminated at rates faster than 1.5 mumole/min/g liver. At least two NADPH- and two NADH-dependent cytosolic enzymes are responsible for nitrosochloramphenicol reduction. Determination of the kinetic parameters of these enzymes by stop-flow analysis revealed the contribution of enzymes, one of it being alcohol dehydrogenase, with Michaelis constants in the micromolar range. Despite this high reducing capacity, about 10% of nitrosochloramphenicol reacted with GSH under formation of glutathionesulfinamidochloramphenicol and GSSG released from the liver into bile and venous effluent. At high nitrosochloramphenicol load these reactions led to glutathione depletion of the liver, caused membrane damage, and impaired bile production. At low nitrosochloramphenicol load, i.e. below 0.5 mumole/min/g, no relevant nitrosochloramphenicol passed the liver. These data together with the previously reported reactions of nitrosochloramphenicol within human blood suggest that nitrosochloramphenicol, if formed at all in the intestine or liver, is rather unlikely to be transferred to the critical target.
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PMID:Formation and disposition of nitrosochloramphenicol in rat liver. 405 15

It has been suggested that nitrosochloramphenicol (NOCAP), a possible metabolite of chloramphenicol (CAP), may be involved in CAP-induced aplastic anemia. We found that NOCAP was rapidly eliminated from human blood in vitro (more than 90% in less than 15 sec). Analysis of the different reactions showed that 5% of NOCAP was covalently bound to plasma proteins, mainly to albumin, the remainder being metabolized in red cells. The most important reaction in red cells was the very rapid adduct formation with GSH (k = 5,500 M-1S-1), yielding presumably a semimercaptal which either isomerized to a sulfinamide (GSONHCAP, k = 0.05 s-1) or was thiolytically cleaved by another GSH molecule with formation of the hydroxylamine (NHOHCAP) and GSSG (k = 7.1 M-1S-1). Another important elimination reaction was the covalent binding of NOCAP to the SH groups of hemoglobin (k = 5M-1S-1), also yielding a sulfinamide. Besides these reactions with thiols, NOCAP was enzymatically reduced to NHOHCAP in the presence of NADPH (Km NADPH = 10(-5) M; Km NOCAP = 10(-4) M; Vmax = 2 mumole/min per ml). This reaction was only effective at NOCAP concentrations below 10(-4)M, probably because of limited NADPH-regeneration. Further reduction of NHOHCAP to NH2CAP was a slow process which did not exceed 0.5 nmole/min per ml. NH2CAP was mainly formed from GSONHCAP, a reaction which depended on NADPH and the presence of hemolysate, indicating an enzymatic reaction. In contrast to smaller nitrosoarenes, NOCAP was a poor ligand for ferrohemoglobin (probably due to steric hindrance by its bulky molecule) and was therefore much more exposed to biotransformation. NOCAP and NHOHCAP formed ferrihemoglobin at a rate 5000 times slower than did phenylhydroxylamine. In contrast to NOCAP, NHOHCAP penetrated slowly the red cell membrane (4 about 5 min), and its disposition in blood was quite ineffective. From these data, it seems likely that most of the NOCAP formed by microorganisms in the intestine or produced in the liver, will be degraded in blood before it can reach the bone marrow.
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PMID:Reactions of nitrosochloramphenicol in blood. 646 52

A 53-yr-old man sequentially developed aplastic anemia from phenytoin and carbamazepine. Both compounds undergo metabolism to potentially toxic arene oxide intermediates. We tested the hypothesis that the patient's adverse reactions were due to a defect in detoxification of such metabolites by challenging his peripheral lymphocytes with drug metabolites generated by a murine hepatic microsomal system in vitro. The patient's cell viability was normal in the absence of drugs. However, his cells showed greater toxicity from both phenytoin and carbamazepine metabolites than did controls. Toxicity was dependent on microsomes and NADPH. Intermediate toxicity was noted in cells from the patient's mother. The results provide the first evidence for a role of arene oxide drug metabolites in aplastic anemia in humans and suggest that enhanced susceptibility to toxicity may be based on an inherited abnormality in metabolite detoxification.
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PMID:Anticonvulsant-induced aplastic anemia: increased susceptibility to toxic drug metabolites in vitro. 683 Oct 50

Fresh-frozen human liver tissue was assayed for its ability to reduce the nitrogroup of R--NO2 to the amine. All 10 livers examined exhibited demonstrable reductase activity. The reduction was potentiated by NADPH and abolished by boiling the liver homogenates. The nitroreductase activity varied among the different livers by as much as severalfold. These findings show that ability of the human liver to reduce R--NO2 and support the hypothesis that certain toxic intermediates of the nitroreduction of R--NO2 may be responsible for the aplastic anemia associated with this drug.
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PMID:The nitroreduction of chloramphenicol by human liver tissue. 689 61

Reduction of the nitro group of chloramphenicol (CAP) gives rise to more highly reactive intermediates which may in involved in the aplastic anemia associated with CAP use. One such intermediate, nitroso-chloramphenicol (NO-CAP), has been found to be a potent agent for mediating degradation of isolated DNA. In a reaction mixture containing 100 microM NO-CAP, 100 microM CuCl2, and 5 mM NADH, 7 micrograms of Escherichia coli [3H]DNA was completely degraded to acid-soluble fragments in 30 min. Damage to DNA was in the form of single-stranded scissions. The requirement for copper was specific, and copper chelating reagents blocked the degradation. The need for a reducing agent could be met equally well by NADH or NADPH, but not by sulfhydryl reagents such as glutathione, dithiothreitol and 2-mercaptoethanol. Oxygen was also necessary for the NO-CAP mediated DNA damage, with reduced forms of oxygen participating in the reaction. A role for H2O2 was indicated by the inhibition of the degradation seen when catalase was included in the mixture. Hydroxyl radicals are known to be produced in the reaction of H2O2 with certain transition metals. Scavangers of hydroxyl radicals also inhibited strand-scission, suggesting that the radicals may be the primary agents in DNA degradation. The importance of the nitroso moiety of NO-CAP was evidenced by the lack of DNA damage seen when NO-CAP was replaced by CAP under the conditions tested.
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PMID:Degradation of isolated deoxyribonucleic acid mediated by nitroso-chloramphenicol. Possible role in chloramphenicol-induced aplastic anemia. 712 41