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

In 1916 a relationship was postulated between the occurrence of aplastic anaemia in cattle and the soy bean meal that they had been fed, which had been extracted with trichloroethylene. The toxic compound was later identified as S-(1,2-dichlorovinyl)-L-cysteine (DCV-Cys). In addition to effects on the hemopoietic system it also produced nephrotoxicity in calves. In rats only renal tubular necrosis was found. Further research demonstrated that other halogenated hydrocarbons produced similar nephrotoxicity. The haloalkenyl cysteine-S-conjugates (Cys-S-conjugates) have extensively been studied; this has provided new insight into the biochemical processes that lead to nephrotoxicity. It has been shown that a combination of transport processes and specific metabolic pathways, resulting in reactive intermediates that bind to cellular macromolecules, makes the kidney vulnerable to the noxious effects of the haloalkenyl Cys-S-conjugates. The first part of this review gives a brief overview of the bioactivation of the haloalkenes; in the second part the present knowledge of the underlying mechanisms of cytotoxicity will be outlined.
 ...
PMID:Nephrotoxicity of halogenated alkenyl cysteine-S-conjugates. 194 81

In this brief review, we have focused on the relevance of the data on cysteine conjugate toxicity to the potential hazard of bound drug residues. A resonable scenario, based on assumptions as well as literature data, has been presented for the release of cysteine conjugates of drug residues from protein. Furthermore, we have presented evidence that should this occur, the conjugate would be bioavailable. Finally, the mechanisms which could lead to cysteine conjugate-induced toxicity have been discussed. The question which must be answered is, how realistic is the treat of toxicity to the consumer from cysteine-bound drug residues in food products? Based on the data presented here, the danger is minimal, though it cannot be excluded. This is particularly true of the potential for renal complications. However, an important caveat which must not be overlooked is the marked species differences in cysteine conjugate toxicity. Though S-(1,2LD50-dichlorovinyl)-L-cysteine (DCVC) is a renal toxin in rodent models (LD50 = 66-83 mg/kg) [88], a single dose of 4-5 mg/kg causes fatal aplastic anemia in calves [44,59]. Though such a response has never been reported for any other cysteine conjugate, these data must be reckoned with if attempts are made to place acceptable limits on the amount of residues allowable in food products.
 ...
PMID:Is the toxicity of cysteine conjugates formed during mercapturic acid biosynthesis relevant to the toxicity of covalently bound drug residues? 210 45

Almost 40 years ago, it was reported that cattle-feed which had been extracted with hot trichloroethylene and then fed to calves produced renal injury and a fatal aplastic anaemia. The toxic factor was subsequently identified as S-(1,2-dichlorovinyl)-L-cysteine (DCVC). These original findings have been confirmed, a single intravenous dose of DCVC at 4 mg/kg, or 0.4 mg/kg intravenously per day administered for 10 days to calves produced aplastic anaemia, and renal injury after a single dose of 4 mg/kg. The toxicity to calves of a number of other haloalkene cysteine conjugates has been examined to ascertain whether, like DCVC, they produce bone marrow and renal injury. Intravenous administration of the N-acetyl cysteine conjugate of DCVC produced renal but not bone marrow injury at a molar equivalent dose to DCVC, indicating that the calf can deacetylate the mercapturic acid and further that sufficient chemical had reached the kidney to be a substrate for the enzyme cysteine conjugate beta-lyase. However, intravenous administration of the alpha-methyl analogue of DCVC, which cannot undergo metabolism via the enzyme cysteine conjugate beta-lyase, was without toxicity at doses about five-fold higher than DCVC. These latter findings provide strong evidence that metabolism of DCVC via the enzyme beta-lyase is necessary for bone marrow and renal injury to occur. The cysteine conjugates of perchloroethylene and hexachloro-1,3-butadiene(HCBD) when given intravenously to calves at molar equivalent doses to DCVC, or above, did not produce either bone marrow or renal injury. In contrast, intravenous administration of the cysteine conjugate of tetrafluoroethylene (TFEC) produced severe renal tubular injury in calves without affecting the bone marrow. In vitro studies with these haloalkene cysteine conjugates showed, like DCVC, that they were good substrates for calf renal cysteine conjugate beta-lyase and toxic to renal cells as judged by their ability to reduce organic anion and cation transport by slices of calf renal cortex and inhibit the renal enzyme glutathione reductase. Calves were also dosed either orally or intravenously with HCBD to assess its toxicity. HCBD at higher molar equivalent doses than DCVC produced mid-zonal necrosis in the liver, renal tubular necrosis but no bone marrow injury in calves. The key findings emerging from these studies are (1) that none of the other cysteine conjugates, at molar equivalent doses to DCVC and above, produce bone marrow injury in calves, (2) TFEC produced only renal injury, suggesting that sufficient of the other conjugates had not reached the kidney for metabolism by beta-lyase to produce cytotoxicity and (3) that HCBD itself is more toxic than its cysteine or mercapturic acid conjugate, suggesting that pharmaco-kinetics and disposition are important factors in determining the toxicity of these conjugates to calves. Further studies are needed to understand the basis for the selective toxicity of DCVC to the bone marrow of calves.
 ...
PMID:Bone marrow and renal injury associated with haloalkene cysteine conjugates in calves. 887 Sep 53

Congenital amegakaryocytic thrombocytopenia (CAMT) without physical anomalies is a rare disease, presenting isolated thrombocytopenia and megakaryocytopenia in infancy, which can evolve into aplastic anemia and leukemia. Recently, two heterozygous truncating mutations of the thrombopoietin (TPO) receptor MPL, coded by the c-mpl gene, were identified in a 10-year-old Japanese patient with CAMT transmitted in an autosomal recessive manner. Here, we report for the first time two different MPL amino-acid substitutions in a 2-year-old Italian boy with CAMT and compound heterozygosis for two (c-mpl point mutations. C-to-T transitions were detected on exons 5 and 12 at the 769 and 1904 cDNA nucleotide positions, respectively. The mutation in exon 5 substitutes an arginine with a cysteine (R257C) in the extracellular domain, 11 amino acids distant from the WSXWS motif conserved in the cytokine-receptor superfamily. The mutation in exon 12 substitutes a proline with a leucine (P635L) in the last amino acid of the C-terminal intracellular domain, responsible for signal transduction. As in the Japanese family, the mutations were both transmitted from the parents. TPO plasma levels were highly increased in the patient. The patient's 7-year-old brother, who was a candidate donor for allografting, turned out to be an asymptomatic heterozygous carrier of P635L and showed defective megakaryocyte colony formation from bone-marrow progenitor cells. The present study provides important confirmation that CAMT can be associated with (c-mpl) mutations.
 ...
PMID:Compound heterozygosity for two different amino-acid substitution mutations in the thrombopoietin receptor (c-mpl gene) in congenital amegakaryocytic thrombocytopenia (CAMT). 1107 83

The stem cells of the bone marrow have the capacity for both self-renewal and derivation of all the blood cell lineages. Consequently, toxicity to these cells can result in neutropenia, agranulocytosis, thrombocytopenia, pancytopenia, or aplastic anemia. Many anticancer drugs adversely affect the bone marrow, and neutropenia is a common limiting factor in dose escalation. In this review, we discuss agents that appear to have potential as bone marrow sparing agents. Computerized catalogs of the National Library of Medicine and Medline were searched for reports on low-molecular-weight compounds that detailed effects on the hematopoietic progenitor cells. The most promising agents are the endogenous peptides p-glutamic acid-glutamic acid-aspartic acid-cysteine-lysine and acetyl-serine-aspartic acid-lysine-proline, and the exogenous compounds amifostine and ammonium trichloro[dioxoethylene-O,O']tellurate, but several others are also discussed. These compounds preserve stem cell function in the presence of antineoplastic drugs of diverse pharmacological classes, and they do so by various mechanisms of action. Their present status in clinical practice is also detailed. More needs to be learned about their mechanisms of action and therapeutic potential, but the results are encouraging for some of these compounds and more clinical trials should be expected.
 ...
PMID:Bone marrow stem cell protection from chemotherapy by low--molecular-weight compounds. 1116 51

Dyskeratosis congenita (DC) is a multisystem bone marrow failure syndrome characterized by a triad of mucocutaneous abnormalities and a predisposition to cancer. The genetic basis of DC remains unknown in more than 60% of patients. Mutations have been identified in components of the telomerase complex (dyskerin, TERC, TERT, NOP10, and NHP2), and recently in one component of the shelterin complex TIN2 (gene TINF2). To establish the role of TINF2 mutations, we screened DNA from 175 uncharacterised patients with DC as well as 244 patients with other bone marrow failure disorders. Heterozygous coding mutations were found in 33 of 175 previously uncharacterized DC index patients and 3 of 244 other patients. A total of 21 of the mutations affected amino acid 282, changing arginine to histidine (n = 14) or cysteine (n = 7). A total of 32 of 33 patients with DC with TINF2 mutations have severe disease, with most developing aplastic anaemia by the age of 10 years. Telomere lengths in patients with TINF2 mutations were the shortest compared with other DC subtypes, but TERC levels were normal. In this large series, TINF2 mutations account for approximately 11% of all DC, but they do not play a significant role in patients with related disorders. This study emphasises the role of defective telomere maintenance on human disease.
 ...
PMID:TINF2 mutations result in very short telomeres: analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes. 1866 93

We recently identified 2 siblings afflicted with idiopathic, autosomal recessive aplastic anemia. Whole-exome sequencing identified a novel homozygous missense mutation in thrombopoietin (THPO, c.112C>T) in both affected siblings. This mutation encodes an arginine to cysteine substitution at residue 38 or residue 17 excluding the 21-amino acid signal peptide of THPO receptor binding domain (RBD). THPO has 4 conserved cysteines in its RBD that form 2 disulfide bonds. Our in silico modeling predicts that introduction of a fifth cysteine may disrupt normal disulfide bonding to cause poor receptor binding. In functional assays, the mutant-THPO-containing media shows two- to threefold reduced ability to sustain UT7-TPO cells, which require THPO for proliferation. Both parents and a sibling with heterozygous R17C change have reduced platelet counts, whereas a sibling with wild-type sequence has normal platelet count. Thus, the R17C partial loss-of-function allele results in aplastic anemia in the homozygous state and mild thrombocytopenia in the heterozygous state in our family. Together with the recent identification of THPO receptor (MPL) mutations and the effects of THPO agonists in aplastic anemia, our results have clinical implications in the diagnosis and treatment of patients with aplastic anemia and highlight a role for the THPO-MPL pathway in hematopoiesis in vivo.
...
PMID:Exome sequencing reveals a thrombopoietin ligand mutation in a Micronesian family with autosomal recessive aplastic anemia. 2408 63

We detected a somatic mutation in the HLA-B gene in a Czech hematooncological patient. We followed the development of this somatic mutation during the transition from severe aplastic anaemia through to myelodysplastic syndrome to acute myeloid leukaemia until haploidentical related transplantation. The somatic mutation differs from HLA-B*14:02 in exon 3 resulting in an exchange from cysteine to serine at position 101 of the mature protein. Homology modelling of mutated S101 in HLA-B*14 indicated possible conformational changes, which might also result in an aberrant expression. The assumption is that somatic mutation arose as a possible result of a selection mediated by a protective immune response against leukaemia.
 ...
PMID:The formation of a somatic mutation in the HLA-B gene throughout the development of the disease from severe aplastic anaemia to acute myeloid leukaemia. 3173 47

There are a number of newly described and emerging disease syndromes affecting the domestic ferret, and the purpose of this article is to make veterinarians aware of these diseases. A recently described systemic coronavirus infection appears to be a variant of the ferret enteric coronavirus and is currently termed "ferret infectious peritonitis." Disseminated immunopathologic myositis, aplastic anemia/bone marrow aplasia, acute hemorrhagic syndrome, and oral ulcerations are also described, although the exact etiologies for these diseases have yet to be determined. There appears to be at least 2 important amino acid metabolism deficiencies in ferrets: hindlimb weakness in older ferrets (L-carnitine) and cysteine urolithiasis. Ferrets have recently been found to be susceptible to H1N1 influenza, so knowledge regarding this zoonotic disease is essential for veterinarians working with these animals. A novel Mycoplasma spp. has also recently been identified in ferrets with chronic respiratory problems that originated from one breeding colony. Because these diseases are still being investigated, practitioners who treat a ferret patient exhibiting clinical signs consistent with any of the conditions mentioned are encouraged to contact people who are knowledgeable of that particular illness.
 ...
PMID:Emerging Ferret Diseases. 3228 74