Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1,3 Butadiene (BD) is a colorless gas used in the production of synthetic rubber and plastics. BD is carcinogenic in rats and mice, however, there are striking species differences in cancer potency and spectrum of tumors, with mice being more susceptible to tumor induction than rats. Epidemiology studies suggest an excess incidence of leukemia in workers in the styrene-butadiene rubber industry. Consideration of mechanisms of BD carcinogenicity can provide insights into differences in cancer potency between rodents and serve to elucidate the extent to which BD exposure may cause cancer in humans. Mechanistic research in the areas of biochemical toxicology, molecular biology, molecular dosimetry, and susceptibility factors can impact BD cancer risk assessment for humans. This research has focused on quantitating species differences in the metabolism of BD and BD epoxides, defining molecular lesions produced by BD epoxides, identifying biomarkers for BD exposure to explore metabolic pathways in humans, and determining potential risk factors for sensitive subpopulations. BD is activated by P450 isozymes, including CYP2E1, to at least two genotoxic metabolites, epoxybutene (EB) and diepoxybutane (DEB). Dosimetry data from several laboratories on EB and DEB following inhalation exposure to BD indicate that blood concentrations of EB were four-eight-fold higher in mice compared with rats and that blood concentrations of DEB were 25-100-fold higher in mice than in rats. The higher levels of these two DNA-reactive metabolites in mice compared with rats probably contribute to the species differences in carcinogenic effects of BD between mice and rats. In vitro metabolism studies of BD in rats, mice, and human tissues indicate that there are significant quantitative species differences in the metabolic activation of BD to EB and DEB and the detoxication of EB and DEB. Activation/detoxication ratios calculated using in vitro kinetic constants reveal that ratios in mice were greater than in both rats and humans. In vitro data are consistent with in vivo dosimetry data and cancer potency for rodents, and suggest that humans may be at a decreased risk. Data on mutagenicity and mutational spectra of BD epoxides show mechanistic differences between EB- and DEB-induced mutational events suggesting involvement of DEB in the development of cancer. Concentrations of DEB that are genotoxic in vitro are within the range of concentrations measured in mice in vivo, whereas concentrations of EB that are genotoxic in vitro are ten-100-fold greater than concentrations observed in vivo. Characterization of molecular events indicate that EB-induced genotoxicity is due to point mutations and small deletions, while DEB induces point mutations, small deletions, and large-scale deletions involving many base pairs. The extent to which epoxybutanediol is involved in BD carcinogenesis is not known. Molecular dosimetry studies in rodents and humans have focused on urinary metabolites and DNA and hemoglobin adducts. Data from these studies are consistent with in vivo and in vitro metabolism data providing further support for the differences in metabolic activation and deactivation of BD and BD epoxides across species and the role of DEB in tumor development. Research on potential susceptibility factors points to other P450 isozymes, in addition to CYP2E1, that are involved in both the metabolic activation and mutagenicity of BD. Taken together, mechanistic data on BD toxicokinetics and toxicodynamics provide an integrated insight into critical steps in initiation of cancer, metabolites responsible for cancer, sensitive biomarkers for exposure, and potential risk factors for individual susceptibility. Available evidence suggests that BD is unlikely to be a human carcinogen at the low exposure concentrations currently encountered in the environment or workplace.
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PMID:Insights into the toxicokinetics and toxicodynamics of 1,3-butadiene. 1139 15

The human cytochrome P450 (CYP) metabolizes more than 100 structurally diverse exogenous and endogenous molecules. The CYP3A5 is a major P450 enzyme in the liver and represents 50% of the total hepatic CYP3A content in people expressing CYP3A5. The single nucleotide polymorphisms in CYP3A5*3 and CYP3A5*6 that resulted in the absence of CYP3A5 from tissues were noted in some people. Polymorphisms of potential relevance to leukemia and myelodysplastic syndrome (MDS) have been described for various CYP. The bone marrow and/or peripheral blood from 188 acute myeloid leukemia (AML) patients, 101 chronic myeloid leukemia (CML), 40 MDS, and 270 normal controls were analyzed by a PCR-RFLP assay to evaluate the association of the CYP3A5 polymorphisms with myeloid leukemia. Our data showed that 15/188 (8%), 8/101 (7.9%), and 3/40 (7.5%) of the patients (i.e., 188 AML, 101 CML, 40 MDS) were CYP3A5*1/*1; 88/188 (46.8%), 47/101 (46.5%), and 20/40 (50%) were CYP3A5*1/*3; and 85/188 (45.2%), 46/101 (45.5%), and 17/40 (42.5%) carried the CYP3A5*3/*3 genotype, respectively. CYP3A5*6 was not found in any of the patients' specimens. Similar frequencies of CYP3A5*3 were observed in the leukemic patients and normal controls. Consequently, the finding suggests that the CYP3A5 polymorphism was not associated with the risk of myeloid leukemia.
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PMID:Polymorphism analysis of CYP3A5 in myeloid leukemia. 1183 1

NAD(P)H:quinone oxidoreductase (NQO1) catalyzes the two- or four-electron reduction of numerous endogenous and environmental quinones (e.g., the vitamin E alpha-tocopherol quinone, menadione, benzene quinones). In laboratory animals treated with various environmental chemicals, inhibition of NQO1 metabolism has long been known to increase the risk of toxicity or cancer. Currently, there are 22 reported single-nucleotide polymorphisms (SNPs) in the NQO1 gene. Compared with the human consensus (reference, "wild-type") NQO1*1 allele coding for normal NQO1 enzyme and activity, the NQO1*2 allele encodes a nonsynonymous mutation (P187S) that has negligible NQO1 activity. The NQO1*2 allelic frequency ranges between 0.22 (Caucasian) and 0.45 (Asian) in various ethnic populations. A large epidemiologic investigation of a benzene-exposed population has shown that NQO1*2 homozygotes exhibit as much as a 7-fold greater risk of bone marrow toxicity, leading to diseases such as aplastic anemia and leukemia. The extent of the contribution of polymorphisms in other genes involved in the metabolism of benzene and related compounds-such as the P450 2E1 (CYP2E1), myeloperoxidase (MPO), glutathione-S-transferase (GSTM1, GSTT1), microsomal epoxide hydrolase (EPHX1), and other genes-should also be considered. However, it now seems clear that a lowered or absent NQO1 activity can increase one's risk of bone marrow toxicity, after environmental exposure to benzene and benzene-like compounds. In cancer patients, the NQO1*2 allele appears to be associated with increased risk of chemotherapy-related myeloid leukemia. Many other epidemiological studies, attempting to find an association between the NQO1 polymorphism and one or another human disease, have now begun to appear in the medical literature.
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PMID:NAD(P)H:quinone oxidoreductase (NQO1) polymorphism, exposure to benzene, and predisposition to disease: a HuGE review. 1188 82

Etoposide is a DNA topoisomerase II inhibitor widely used in the treatment of a variety of malignancies that is also associated with therapy-related leukemia. The cytochrome P450 (P450)-derived catechol and quinone metabolites of etoposide may be important in the damage to the MLL (mixed lineage leukemia) gene and other genes resulting in leukemia-associated chromosomal translocations. Kinetic analysis of catechol formation by recombinant P450s was determined using liquid chromatography/selected reaction monitoring/mass spectrometry. CYP3A4 was found to play a major role in etoposide metabolism (K(m) = 77.7 +/- 27.8 microM; V(max) = 314 +/- 84 pmol of catechol/min/nmol of P450). However, CYP3A5 (K(m) = 13. 9 +/- 3.1 microM; V(max) = 19.4 +/- 0.4 pmol of catechol/min/nmol of P450) may be involved in etoposide metabolism at therapeutic concentrations of free drug. Other P450s do not appear to be involved in etoposide catechol formation. Real-time polymerase chain reaction and Western blot analysis revealed significantly increased CYP3A4 mRNA and protein levels in hepatocytes treated with 10 microM rifampicin compared with untreated cells, but only modest effects of rifampicin on CYP3A5 induction. Etoposide (40, 5, 1, and 0.25 microM) caused a slight increase in CYP3A4 mRNA in three of five batches of hepatocytes but did not result in proportionately increased CYP3A4 protein levels. At high concentrations, etoposide induced only a modest increase in CYP3A5 mRNA and protein levels in four of five batches of hepatocytes. Alternatively, coadministration of other drugs with etoposide may account for the increase in etoposide catechol formation during therapy with etoposide.
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PMID:Kinetics and regulation of cytochrome P450-mediated etoposide metabolism. 1531 41

We described here four patients diagnosed with Philadelphia chromosome positive (Ph+) leukemia, consisting of chronic myeloid leukemia (CML) (n=2) and Ph+ acute lymphoblastic leukemia (ALL) (n=2). All patients were treated with imatinib mesylate (300-400 mg/day) for the treatment of relapsed CML after allogeneic hematopoietic stem cell transplantation (SCT) (n=2), relapsed Ph+ ALL after SCT (n=1), and Ph+ ALL preceding SCT (n=1). Significant clinical and molecular responses were observed in all patients and three of them achieved sustained molecular remission. Imatinib was well tolerated and did not induce noticeable graft versus host disease although one patient presented severe skin rash (Grade III). Notably, serum cyclosporine A concentration increased after the initiation of imatinib treatment, probably through competitive inhibition of P450 3A4 isoenzyme. Our data suggest that imatinib in conjunction with SCT for the Ph+ leukemia may be a promising treatment strategy.
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PMID:Imatinib mesylate in conjunction with allogeneic hematopoietic stem cell transplantation in patients with Philadelphia chromosome positive leukemias: report of 4 cases. 1532 66

Individual differences in drug efficacy or toxicity can be influenced by genetic factors. We investigated whether polymorphisms of pharmacogenes that interfere with metabolism of drugs used in conditioning regimen and graft-versus-host disease (GvHD) prophylaxis could be associated with outcomes after HLA-identical hematopoietic stem cell transplantation (HSCT). Pharmacogenes and their polymorphisms were studied in 107 donors and patients with leukemia receiving HSCT. Candidate genes were: P450 cytochrome family (CYP2B6), glutathione-S-transferase family (GST), multidrug-resistance gene, methylenetetrahydrofolate reductase (MTHFR) and vitamin D receptor (VDR). The end points studied were oral mucositis (OM), hemorrhagic cystitis (HC), toxicity and venoocclusive disease of the liver (VOD), GvHD, transplantation-related mortality (TRM) and survival. Multivariate analyses, using death as a competing event, were performed adjusting for clinical factors. Among other clinical and genetic factors, polymorphisms of CYP2B6 genes that interfere with cyclophosphamide metabolism were associated with OM (recipient CYP2B6(*)4; P=0.0067), HC (recipient CYP2B6(*)2; P=0.03) and VOD (donor CYP2B6(*)6; P=0.03). Recipient MTHFR polymorphisms (C677T) were associated with acute GvHD (P=0.03), and recipient VDR TaqI with TRM and overall survival (P=0.006 and P=0.04, respectively).Genetic factors that interfere with drug metabolisms are associated with treatment-related toxicities, GvHD and survival after HLA-identical HSCT in patients with leukemia and should be investigated prospectively.
Leukemia 2009 Mar
PMID:Association of drug metabolism gene polymorphisms with toxicities, graft-versus-host disease and survival after HLA-identical sibling hematopoietic stem cell transplantation for patients with leukemia. 1900 82

The development of techniques allowing the growth of primordial follicles to mature follicles in vitro has much potential for both reproductive medicine and developmental research. However, human primordial and preantral follicles fail to grow after isolation from the surrounding ovarian stroma. Granulosa cells, which normally undergo apoptosis after ovulation, contain a subpopulation of ovarian follicular cells remaining viable in vitro over prolonged periods when cultured in the presence of leukemia-inhibiting factor. However, when cultured as monolayers, they progressively lose all their characteristics, such as follicle-stimulating hormone receptor and cytochrome P450-aromatase. Here, we describe a three-dimensional culture system containing type I collagen, which, together with leukemia-inhibiting factor, allowed the survival and growth of a subpopulation of granulosa cells isolated from mature ovarian follicles and supported them to proliferate into spherical structures exhibiting steroidogenic capacity, as demonstrated by P450-aromatase and 3beta-hydroxysteroid dehydrogenase. After transplantation into the ovaries of immunodeficient mice, these cells became localized preferentially within antral follicles and the prolonged expression of follicle-stimulating hormone receptor was confirmed as well. With this optimization of the culture conditions, an environment was created, which acts as a niche closely mimicking the development of early ovarian follicles in vitro.
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PMID:A novel three-dimensional culture system allows prolonged culture of functional human granulosa cells and mimics the ovarian environment. 2010 57

Xenobiotic-metabolizing genes (e.g., Cytochromes P450, GST, NAT2, and NQO1), folate metabolism genes (e.g., MTHFR and MTRR), and major histocompatibility complex genes (e.g., HLA-DQA1) play multiple roles in the organism functioning. In addition, AB0 is the most clinically significant high-polymorphic gene in transfusion and transplantation medicine. Epidemiological data show that allele frequencies of these genes exhibit ethnic and geographic diversity. Besides, little is known about frequency distribution of the major polymorphic variants in native Russians. We developed biological microchips that allow us to analyze a spectrum of allelic variants in 12 different genes: CYP1A1, CYP2D6, CYP2C9, CYP2C19, GSTT1, GSTM1, MTHFR, MTRR, NQO1, NAT2, HLA-DQA1, and AB0. Using this composite methodological platform we have studied 352 DNA samples from healthy native Russian volunteers. The allelic frequencies of gene polymorphisms obtained are close to allelic frequencies observed in some European populations, as published earlier. These data were used in comparative studies to determine predisposition to tuberculosis, lymphoma, and leukemia in adults and to childhood acute leukemia. The HLA-DQA1 and AB0 allele frequencies were used to estimate forensic population parameters for these loci.
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PMID:Microarray-based detection of CYP1A1, CYP2C9, CYP2C19, CYP2D6, GSTT1, GSTM1, MTHFR, MTRR, NQO1, NAT2, HLA-DQA1, and AB0 allele frequencies in native Russians. 2037 52

FD-891 is a 16-membered cytotoxic antibiotic macrolide that is especially active against human leukemia such as HL-60 and Jurkat cells. We identified the FD-891 biosynthetic (gfs) gene cluster from the producer Streptomyces graminofaciens A-8890 by using typical modular type I polyketide synthase (PKS) genes as probes. The gfs gene cluster contained five typical modular type I PKS genes (gfsA, B, C, D, and E), a cytochrome P450 gene (gfsF), a methyltransferase gene (gfsG), and a regulator gene (gfsR). The gene organization of PKSs agreed well with the basic polyketide skeleton of FD-891 including the oxidation states and alpha-alkyl substituent determined by the substrate specificities of the acyltransferase (AT) domains. To clarify the involvement of the gfs genes in the FD-891 biosynthesis, the P450 gfsF gene was inactivated; this resulted in the loss of FD-891 production. Instead, the gfsF gene-disrupted mutant accumulated a novel FD-891 analogue 25-O-methyl-FD-892, which lacked the epoxide and the hydroxyl group of FD-891. Furthermore, the recombinant GfsF enzyme coexpressed with putidaredoxin and putidaredoxin reductase converted 25-O-methyl-FD-892 into FD-891. In the course of the GfsF reaction, 10-deoxy-FD-891 was isolated as an enzymatic reaction intermediate, which was also converted into FD-891 by GfsF. Therefore, it was clearly found that the cytochrome P450 GfsF catalyzes epoxidation and hydroxylation in a stepwise manner in the FD-891 biosynthesis. These results clearly confirmed that the identified gfs genes are responsible for the biosynthesis of FD-891 in S. graminofaciens.
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PMID:Cloning and characterization of the biosynthetic gene cluster of 16-membered macrolide antibiotic FD-891: involvement of a dual functional cytochrome P450 monooxygenase catalyzing epoxidation and hydroxylation. 2058 23

Imatinib, a selective tyrosine kinase inhibitor, is the first line treatment against chronic myelogenous leukaemia (CML) and gastrointestinal stromal tumors (GIST). Several fatal cases have been associated with imatinib hepatotoxicity. Acetaminophen, an over-the-counter analgesic, anti-pyretic drug, which can cause hepatotoxicity, is commonly used in cancer pain management. We assessed renal and hepatic toxicity after imatinib and acetaminophen co-administration in a preclinical model. Four groups of male ICR mice (30-35 g) were fasted overnight and administered either saline solution orally (baseline control), imatinib 100 mg/kg orally (control), acetaminophen 700 mg/kg intraperitoneally (positive control) or co-administered imatinib 100 mg/kg orally and acetaminophen 700 mg/kg intraperitoneally (study group), and sacrificed at 15 min, 30 min, 1 h, 2 h, 4 h and 6 h post-administration (n = 4 per time point). The liver and kidneys were harvested for histopathology assessment. The liver showed reversible cell damage like feathery degeneration, microvesicular fatty change, sinusoidal congestion and pyknosis, when imatinib or acetaminophen were administered separately. The damage increased gradually with time, peaked at 2 h but resolved by 4 h. When both drugs were administered concurrently, the liver showed irreversible damage (cytolysis, karyolysis and karyorrhexis) which did not resolve by 6 h. Very minor renal changes were observed. Acetaminophen and imatinib co-administration increased hepatoxicity which become irreversible, probably due to shared P450 biotransformation pathways and transporters in the liver.
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PMID:Histopathological study of the hepatic and renal toxicity associated with the co-administration of imatinib and acetaminophen in a preclinical mouse model. 2061 20


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