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

Benzene is an important industrial chemical. At certain levels, benzene has been found to produce aplastic anemia, pancytopenia, myeloblastic anemia and genotoxic effects in humans. Metabolism by cytochrome P450 monooxygenases and myeloperoxidase to hydroquinone, phenol, and other metabolites contributes to benzene toxicity. Other xenobiotic substrates for cytochrome P450 can alter benzene metabolism. At high concentrations, toluene has been shown to inhibit benzene metabolism and benzene-induced toxicities. The present study investigated the genotoxicity of exposure to benzene and toluene at lower and intermittent co-exposures. Mice were exposed via whole-body inhalation for 6h/day for 8 days (over a 15-day time period) to air, 50 ppm benzene, 100 ppm toluene, 50 ppm benzene and 50 ppm toluene, or 50 ppm benzene and 100 ppm toluene. Mice exposed to 50 ppm benzene exhibited an increased frequency (2.4-fold) of micronucleated polychromatic erythrocytes (PCE) and increased levels of urinary metabolites (t,t-muconic acid, hydroquinone, and s-phenylmercapturic acid) vs. air-exposed controls. Benzene co-exposure with 100 ppm toluene resulted in similar urinary metabolite levels but a 3.7-fold increase in frequency of micronucleated PCE. Benzene co-exposure with 50 ppm toluene resulted in a similar elevation of micronuclei frequency as with 100 ppm toluene which did not differ significantly from 50 ppm benzene exposure alone. Both co-exposures - 50 ppm benzene with 50 or 100 ppm toluene - resulted in significantly elevated CYP2E1 activities that did not occur following benzene or toluene exposure alone. Whole blood glutathione (GSH) levels were similarly decreased following exposure to 50 ppm benzene and/or 100 ppm toluene, while co-exposure to 50 ppm benzene and 100 ppm toluene significantly decreased GSSG levels and increased the GSH/GSSG ratio. The higher frequency of micronucleated PCE following benzene and toluene co-exposure when compared with mice exposed to benzene or toluene alone suggests that, at the doses used in this study, toluene can enhance benzene-induced clastogenic or aneugenic bone marrow injury. These findings exemplify the importance of studying the effects of binary chemical interactions in animals exposed to lower exposure concentrations of benzene and toluene on benzene metabolism and clastogenicity. The relevance of these data on interactions for humans exposed at low benzene concentrations can be best assessed only when the mechanism of interaction is understood at a quantitative level and incorporated within a biologically based modeling framework.
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PMID:Genotoxicity of intermittent co-exposure to benzene and toluene in male CD-1 mice. 1845 11