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)

The cytochromes P450 may represent the major metabolic frontier between the environment and the body. The recent discovery of interpatient differences in P450 profile has provided a plausible explanation for heterogeneous dosing requirements for some individual drugs. The heterogeneity in P450 profiles appears to also account for some "idiosyncratic" drug reactions, especially hepatotoxicity. An important challenge for the future is the development of safe and noninvasive tests capable of determining patients' P450 profiles. It is likely that such tests will greatly facilitate individualization of dosing of many drugs in the future. In addition, such tests should be useful in identifying patients likely to develop "idiosyncratic" toxicity to specific drugs. Finally, it seems likely that interpatient differences in P450 profile may at least in part explain interpatient differences in susceptibility to environmental diseases. For example, it may in the future be possible to identify individuals with P450 profiles that render them susceptible to leukemia from xenobiotics such as benzene. Such individuals could be advised not to work in an environment containing these chemicals or, alternatively, to take a medication which reduces their risk by appropriately altering their P450 profile. Identification and in vitro characterization of human P450s is now well underway and may be largely completed within the next decade. However, studies addressing the clinical significance of interpatient differences in P450 profile, as well as the genetic and nongenetic factors that underlie this heterogeneity, are just beginning. This should remain a rewarding area of research for many years to come.
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PMID:Role of cytochromes P450 in drug metabolism and hepatotoxicity. 228 32

Benzene, an important industrial solvent and constituent of unleaded gasoline, causes leukemia and aplastic anemia in humans. Mice are more sensitive than rats to benzene toxicity, though neither species has been shown to respond consistently with benzene-induced leukemia. Benzene biotransformation in liver to phenol, hydroquinone, catechol and/or muconaldehyde is thought to be necessary for its hematotoxicity and/or genotoxicity. Our goal is to develop a mathematical simulation model capable of describing the pathways and kinetics of benzene metabolism by rat and mouse liver microsomes and to assess the role of species metabolic differences in species sensitivity. Microsomes were incubated with 4 microM [U-14C]-benzene or 4 microM [U-14C]phenol. Metabolite production was quantified by extraction into ethyl acetate, HPLC separation and liquid scintillation spectroscopy. After 45 min, mouse liver microsomes converted 20% of the benzene to phenol, 31% to hydroquinone and 2% to catechol. Rat liver microsomes converted 23% of benzene to phenol, 8% to hydroquinone and 0.5% to catechol. Production of hydroquinone and catechol continued for 90 min for mouse liver microsomes, while production by rat liver microsomes had virtually ceased by 90 min. Muconic acid production by mouse liver microsomes was < 0.2% and < 0.04% from benzene and phenol respectively after 90 min. A quantitative simulation model was constructed to describe the in vitro metabolism of benzene, incorporating the reaction sequences: benzene-->phenol-->catechol-->trihydroxybenzene and phenol-->hydroquinone-->trihydroxybenzene. In the model, all of the reaction steps are assumed to be catalyzed by the same enzyme(s), cytochrome(s) P450, and benzene, phenol, hydroquinone and catechol in solution are all assumed to compete, through reversible binding, for the same reaction site(s) on cytochrome(s) P450. The simulation model accurately described both the benzene and phenol kinetic data, supporting this proposed mechanism. In particular, this model suggests that the observed inhibition of benzene on phenol metabolism, and of phenol on benzene metabolism, occurs through competition for a common reaction site, which can also bind catechol and hydroquinone.
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PMID:Benzene and phenol metabolism by mouse and rat liver microsomes. 826 15

All-trans retinoic acid (ATRA) induces remission in patients with acute promyelocytic leukaemia. Other retinoids, including 9-cis- and 13-cis-retinoic acid (9-cis- and 13-cis-RA), are now being evaluated for their therapeutic potential. The elimination of ATRA is partially dependent on cytochrome P450 (P450)-mediated 4-hydroxylation, but the interaction of other retinoids with P450 has not yet been assessed. In the present study 9-cis- and 13-cis-RAs, as well as all-trans-retinol and three isomeric retinals were found to inhibit ATRA 4-hydroxylation in human hepatic microsomes, but the arotinoids acitretin and etretinate were not inhibitors 9-cis- and 13-cis-RA were competitive inhibitors of ATRA 4-hydroxylation (Ki:Km ratios 3.5 +/- 0.8 and 6.3 +/- 0.5, respectively) suggesting that these retinoids are alternate, but inferior, substrates for the P450 enzyme(s) that mediate the activity. The biotransformation of therapeutic retinoids containing the beta-ionone ring system is likely to involve the microsomal ATRA 4-hydroxylase P450.
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PMID:All-trans-retinoic acid 4-hydroxylation in human liver microsomes: in vitro modulation by therapeutic retinoids. 879 29

To study the molecular mechanism of the differentiation induced by retinoic acid (RA) in acute promyelocytic leukemia (APL), we established a new RA-resistant NB4 subline, NB4/RA. The NB4/RA cells were neither differentiated by a single or a combination of RA isoforms, nor by the addition of clotrimazole (P450-inhibitor) or interferon gamma. However, the combination of RA and 8-(4-chlorophenylthio) adenosine cyclic 3',5'-monophosphate (a cAMP analog, 8-CPT-cAMP) induced differentiation. Immunostaining of NB4/RA cells using anti-PML antibody showed a microgranular pattern which was not restored even by the combination of RA and 8-CPT-cAMP, whereas the microgranular pattern in NB4 cells was rapidly restored to the normal speckled pattern by RA. Western blot analysis revealed that RA alone or the combination with 8-CPT-cAMP did not down-regulate PML-RARalpha in NB4/RA cells, which was in contrast to NB4 cells. The PML-RARalpha fusion gene and transcript in NB4/RA cells were conserved as well as the RARalpha gene and transcripts. Sequence analysis of the PML-RARalpha transcript in NB4/RA cells indicated a Pro (CCG) to Leu (CTG) mutation at codon 900 (type L) in AF-2 domain, while the RARalpha transcript had a normal sequence. These data suggest that differentiation of APL by RA is triggered directly through PML-RARalpha, and is associated with its degradation. Furthermore, there might be another mechanism of differentiation which does not require the down-regulation of PML-RARalpha and the restoration of the PML-staining pattern.
Leukemia 1997 Nov
PMID:Mutant AF-2 domain of PML-RARalpha in retinoic acid-resistant NB4 cells: differentiation induced by RA is triggered directly through PML-RARalpha and its down-regulation in acute promyelocytic leukemia. 936 31

Cytochrome P450 3A4, the most abundant P450 form in human liver, exhibits a very broad substrate specificity and is of great importance for drug metabolism. The interindividual difference in the hepatic expression of CYP3A4 is considerable. In order to investigate possible genetic factor(s) causing this variation, the rate of 6beta-hydroxylation of testosterone in human liver microsomes prepared from 46 different human liver samples was determined and the 5'upstream region (+10 to -490 bp) was sequenced from genomic DNA isolated from 39 of these livers. We found a 31-fold variation of the testosterone hydroxylase activity between the samples. However, a very high sequence homology between the CYP3A4 5'-upstream regions sequenced from the 78 different alleles was found. In fact, only three variant nucleotide exchanges were identified, all causing a -290 A-->G mutation (CYP3A4-V) in a so called nifedipine specific element (NFSE). The importance of this element and the polymorphism was evaluated by gel shift analysis. Competition experiments revealed that the binding of nuclear proteins, although having lower affinity to the CYP3A4-V form of the element, was unspecific in nature. In accordance, no influence of this polymorphism was seen on the microsomal testosterone hydroxylase activity in vitro. It is concluded that the promoter region of CYP3A4 is highly conserved, the only polymorphism being in the NFSE, which however does not influence the enzyme expression in liver to a significant degree. This casts doubt of a previously described relationship between the CYP3A4-V allele and cancer in the prostate and leukaemia.
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PMID:Interindividual differences in hepatic expression of CYP3A4: relationship to genetic polymorphism in the 5'-upstream regulatory region. 1033 40

Interleukin 11 (IL-11) is a pleiotropic cytokine with biological activities on many different cell types. Recombinant human IL-11 (rhIL-11) is produced by recombinant DNA technology in Escherichia coli. Both in vitro and in vivo, rhIL-11 has shown effects on multiple hematopoietic cell types. Its predominant in vivo hematopoietic activity is the stimulation of peripheral platelet counts in both normal and myelosuppressed animals. This activity is mediated through effects on both early and late progenitor cells to stimulate megakaryocyte differentiation and maturation. rhIL-11 has been approved for the treatment of chemotherapy-induced thrombocytopenia. The hematopoietic effects of rhIL-11 are most likely direct effects on progenitor cells and megakaryocytes in combination with other cytokines or growth factors. rhIL-11 also induces secretion of acute phase proteins (ferritin, haptoglobin, C-reactive protein, and fibrinogen) from the liver. The induction of heme oxidase and inhibition of several P450 oxidases have been reported from in vitro studies. In vivo, rhIL-11 treatment decreases sodium excretion by the kidney by an unknown mechanism and induces hemodilution. rhIL-11 also exhibits anti-inflammatory effects in a variety of animal models of acute and chronic inflammation, including inflammatory bowel disease, inflammatory skin disease, autoimmune joint disease, and various infection-endotoxemia syndromes. rhIL-11 has trophic effects on non-transformed intestinal epithelium under conditions of mucosal damage. The mechanism of the anti-inflammatory activity of rhIL-11 has been extensively studied. rhIL-11 directly affects macrophage and T cell effector function. rhIL-11 inhibits tumor necrosis factor-alpha (TNF alpha), interleukin 1beta (IL-1beta), interleukin 12 (IL-12), interleukin 6 (IL-6), and nitric oxide (NO) production from activated macrophages in vitro. The inhibition of cytokine production was associated with inhibition of nuclear translocation of the transcription factor, nuclear factor kappa B (NF-kappaB). The block to NF-kappaB nuclear translocation correlates with the ability of rhIL-11 to maintain or enhance production of the inhibitors of NF-kappaB, IkappaB-alpha and IkappaB-beta. In addition to effects on macrophages, rhIL-11 also reduces CD4+ T cell production of Th1 cytokines, such as IFN gamma induced by IL-12, while enhancing Th2 cytokine production. rhIL-11 also blocks IFN gamma production in vivo. The molecular effects of rhIL-11 have also been studied in a clinical trial. Molecular analysis of skin biopsies of patients with psoriasis before and during rhIL-11 treatment demonstrates a decrease in mRNA levels of TNF alpha, IFN gamma and iNOS. These activities suggest that in addition to its thrombopoietic clinical use, rhIL-11 may also be valuable in the treatment of inflammatory diseases. The clinical utility of the anti-inflammatory properties of rhIL-11 is being investigated in patients with Crohn's disease, psoriasis and rheumatoid arthritis. These diseases are believed to be initiated and maintained by activated CD4+ Th1 cells in conjunction with activated macrophages.
Leukemia 1999 Sep
PMID:Hematopoietic, immunomodulatory and epithelial effects of interleukin-11. 1048 79

Carcinogenic polycyclic aromatic hydrocarbons (PAH), such as benzo[a]pyrene (B[a]P), 7,12-dimethylbenz[a]anthracene (DMBA), and dibenzo[a,l]pyrene (DB[a,l]P), are metabolically activated to electrophilically reactive bay or fjord region diol epoxides that bind to the exocyclic amino groups of purine bases in DNA to form stable adducts. In addition, it has been reported that these PAH can be enzymatically oxidized to yield radical cations that form apurinic (AP) sites in DNA via depurinating adducts. The formation of stable adducts and AP sites in DNA of human cells exposed to PAH was examined in cytochrome P450 (P450)-expressing mammary carcinoma MCF-7 cells and in leukemia HL-60 cells, which display a high peroxidase but no P450-mediated activity, after exposure to these PAH. Stable DNA adducts were assessed by (33)P-postlabeling/HPLC analysis, and the induction of AP sites in DNA was analyzed by an aldehyde reactive probe (ARP) and a slot blot method. After exposure for 4 h, the levels of stable DNA adducts were comparable in MCF-7 cells treated with B[a]P and DMBA, but significantly lower than those observed in MCF-7 cells treated with the stronger carcinogen DB[a,l]P. While the levels of stable adducts increased more than 10-fold (B[a]P and DMBA) or 100-fold (DB[a,l]P) after exposure for 24 h, the levels of AP sites remained low after both treatment periods. Thus, the levels of stable adducts were approximately 5-fold higher than the levels of AP sites after treatment with B[a]P or DMBA and more than 100-fold higher in cells exposed to DB[a,l]P for 24 h. None of these carcinogenic PAH formed detectable levels of stable DNA adducts or AP sites in HL-60 cells. The results demonstrate that metabolic activation of B[a]P, DMBA, and DB[a,l]P is catalyzed by P450 enzymes leading to diol epoxides that form predominantly stable DNA adducts but only low levels of AP sites.
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PMID:Formation of stable DNA adducts and apurinic sites upon metabolic activation of bay and fjord region polycyclic aromatic hydrocarbons in human cell cultures. 1064 61

Some six or so physiological systems, essential to normal mammalian life, are involved in poisoning; an intoxication that causes severe injury to any one of them could be life threatening. Reversible chemical reactions showing Scatchard-type binding are exemplified by CO, CN- and cyclodiene neurotoxin insecticide intoxications, and by antigen-antibody complex formation. Haemoglobin (Hb) molecular biology accounts for the allosteric co-operativity and other characteristics of CO poisoning, CN- acts as a powerful cytochrome oxidase inhibitor, and antigen binding in a deep antibody cleft between two domains equipped with epitopes for antigen-binding groups explains hapten-specific immune reactions. Covalent chemical reactions with second-order (SN2) kinetics characterize Hg and Cd poisonings, the reactions of organophosphates and phosphonates with acetylcholinesterase and neurotoxic esterase and the reaction sequence whereby Paraquat accepts electrons and generates superoxide under aerobic conditions. Indirect carcinogens require cytochrome P450 activation to form DNA adducts in target-organ DNA and cause cancer, but a battery of detoxifying enzymes clustered with the P450 system must be overcome. Thus, S-metabolism competes ineffectively with target DNA for reactive vinyl chloride (VC) metabolites, epoxide hydrolase is important to the metabolism and carcinogenicity of alfatoxins and polycyclic aromatic hydrocarbons (benzo[a]pyrene, etc.), and the non-toxic 2-naphthylhydroxylamine N-glucuronide acts as a transport form in 2-naphthylamine bladder cancer. VC liver-cancer pathogenesis is explicable in terms of the presence of the glutathione S-transferase detoxifying system in hepatocytes and its absence from the fibroblastic elements, and of the VC concentrations reaching the liver by different administrative routes. In VC carcinogenicity, chemical reactions give imidazo-cyclization products with nucleoside residues of target DNA, and in benzene leukaemia, Z,Z-muconaldehyde forms cyclic products containing a pyrrole residue linked to purine. Increased HbCO concentrations reduce the O2-carrying capacity of the blood, and the changed shape of the O2-Hb dissociation curve parallels disturbance in O2 unloading. CN- acts on electron transport and paralyses respiration. In telodrin poisoning, preconvulsive glutamine formation abstracts tricarboxylic acid intermediates incommensurately with normal cerebral respiration. Antigen-antibody complexing depletes the antibody titre, available against infection. At high doses of Cd, Cd-thionein filtered through the kidneys is reabsorbed and tubular lesions produced. Some organophosphate insecticides promote irreversible acetylcholinesterase phosphorylation and blockade nerve function, and others react with neurotoxic esterase to cause delayed neuropathy. The evidence for Paraquat pulmonary poisoning suggests a radical mechanism involving three interrelated cyclic reaction stages. The action of N- and O8 (O substituent in 6-position of the purine) demethylases explains deletion mechanisms for DNA-alkyl adducts. DNA-directed synthesis in the presence of ultimate carcinogens provides for an estimation of misincorporations, which implicate the same transversions as those found by direct mutagenicity testing. Chemical carcinogens recognize tissue-sensitive cells and modify their heritable genetic complement. Oncoproteins encoded by activated oncogenes signal the transformation of normal cells into cancer cells. The importance of the H-ras oncogene and p53 tumour-suppressor gene is stressed. Antidotal action is analysed; for example, parenteral glutamine administration to telodrin-intoxicated rats restores the depleted cerebral glutamate level and prevents seizures. Glutamate acts as anticonvulsant in petit mal epilepsy. In general, therefore, the reaction of the toxicant-related substance with the relevant target-tissue macromolecule accounts for the biochemical/biological events at a cellular level a
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PMID:Toxic action/toxicity. 1074 Aug 94

Benzene is an occupational hazard and environmental toxicant found in cigarette smoke, gasoline, and the chemical industry. The major health concern associated with benzene exposure is leukemia. The toxic effects of benzene are dependent on its metabolism by the cytochrome P450 enzyme system. Previous research has identified CYP2E1 as the primary P450 isozyme responsible for benzene metabolism at low concentrations, whereas CYP2B1 is involved at higher concentrations. Our studies using microsomal preparations from human, mouse, and rat indicate that CYP2E1 is the P450 isozyme primarily responsible for benzene metabolism in lung and in liver. CYP2B isozymes have little involvement in benzene metabolism by either lung or liver. Our results also indicate that isozymes of the CYP2F subfamily may play a role in benzene metabolism by lung.
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PMID:Cytochromes P450 involved with benzene metabolism in hepatic and pulmonary microsomes. 1108 83

PCBs are industrial chemicals that continue to contaminate our environment. They cause various toxic effects in animals and in exposed human populations. The mechanisms of toxicity, however, are not completely understood. PCBs are metabolized by cytochromes P450 to mono- and dihydroxylated compounds. Dihydroxy-PCBs can potentially be oxidized to the corresponding quinones. We hypothesized that reactive oxygen species (ROS) are produced by redox reactions of PCB metabolites. We tested several synthetic dihydroxy- and quinoid-PCBs with 1-3 chlorines for their potential to produce ROS in vitro and in HL-60 human leukemia cells, and DNA strand breaks in vitro. All dihydroxy-PCBs tested produced superoxide. The quinones generated superoxide only in the presence of GSH, probably during the autoxidation of the glutathione conjugates. We observed increased superoxide production with decreasing halogenation. Incubation of dihydroxy-PCBs or PCB quinones + GSH with plasmid DNA resulted in DNA strand break induction in the presence of Cu(II). Tests with various ROS scavengers indicated that hydroxyl radicals and singlet oxygen are likely involved in this strand break induction. Finally, dihydroxy- and quinoid PCBs also produced ROS in HL-60 cells in a dose- and time-dependent manner. We conclude that dihydroxylated PCBs, and PCB quinones after reaction with GSH, produce superoxide and other ROS both in vitro and in HL-60 cells, and oxidative DNA damage in the form of DNA strand breaks in vitro. The reactions seen in vitro and in cells may well be a predictor of the toxicity of PCBs in animals.
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PMID:Production of DNA strand breaks in vitro and reactive oxygen species in vitro and in HL-60 cells by PCB metabolites. 1122 76


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