Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.17 (PCE)
 1,301 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Various nucleoside analogues are being used or are being considered for use as therapeutic drugs to inhibit replication of the HTLV-III/LAV virus in infected human cells. Here, the ability of seven nucleoside analogues, a combination of two analogues, and two other therapeutic compounds to induce genotoxic and cytotoxic damage in vivo was evaluated in the mouse bone marrow micronucleus test. Using a 3-consecutive-day oral treatment protocol, almost all of the test chemicals induced a significant increase in the frequency of micronucleated polychromatic erythrocytes (MN-PCE) in male B6C3F1 mice, ranked in decreasing potency as 6-thioguanine greater than Cytarabine HCl greater than 3'-azido-3'-deoxythymidine (AZT)/2',3'-dideoxycytidine combination = AZT greater than Ribavirin = 2',3'-didehydro-3'-deoxythymidine greater than 2',3'-dideoxyadenosine = 2',3'-dideoxycytidine. The frequency of MN-PCE was not increased significantly by treatment with 2',3-dideoxyinosine (DDI) or pentamidine isethionate (PI). The differential ability of AZT and DDI to induce MN in mouse bone marrow was verified from peripheral blood smears prepared from subchronic (90 day) oral studies. The lack of genotoxic activity by DDI was route-specific since, when tested by intraperitoneal injection, a small but significant increase in MN-PCE was observed. A number of these chemicals induced a significant depression in erythropoiesis. However, there was not a significant correlation between the increase in MN-PCE and the depression in the percentage of PCE. This lack of a correlation suggests that factors other than DNA damage may contribute to the inhibition in the rate of erythropoiesis. The presence of increased levels of micronuclei in bone marrow PCE following treatment with various nucleoside analogues suggests that intrinsic genotoxic activity in mammalian cells should be one factor considered during drug selection for AIDS therapy.
Environ Mol Mutagen 1991
PMID:Induction of micronuclei in mouse bone marrow cells: an evaluation of nucleoside analogues used in the treatment of AIDS. 191 12

We have examined published negative control data from 581 papers on micronucleated bone marrow polychromatic erythrocytes (mnPCE) for differences in mean frequency and the frequency distribution profile among the mouse stocks used with the bone marrow micronucleus assay. For the 55 mouse stocks with published micronucleus assay data, the overall mean frequency is 1.95 mnPCE/1,000 PCE (1.95 mnPCE/1,000); for the 13 stocks most commonly used in the assay, it is 1.88 mnPCE/1,000. During the last 5 years, the mnPCE rate for these 13 major stocks has been 1.74 mnPCE/1,000. This current mean frequency is a substantial decrease from the mean of 3.07 mnPCE/1,000 observed for these 13 stocks for data published prior to 1981. Of the major stocks, the highest mean mnPCE negative control frequencies were observed for MS/Ae > BALB/c > C57Bl/6, and the lowest for CD-1 < Swiss Webster. We note that hybrid mouse stocks appear to have lower and less variable negative control frequencies than either of their parent strains and that the negative control frequency for some progeny stocks have diverged significantly from that of the parent stocks. Overall mean negative control frequencies appear to be correlated with breadth of the frequency distribution profile of published mean negative control values. Furthermore, a possible correlation between negative control frequency in the micronucleus assay and sensitivity to clastogens of different mouse strains may be indicated. The databases generated here allow us to define a range of norms for both the historical mean frequency and individual experimental mean frequencies for most stocks, but in particular, for the more commonly used mouse stocks. Our analysis, for the most part, bears out the recommendation of the first Gene-Tox Report on the micronucleus assay that the historical negative control frequency for a mouse stock should fall between 1 and 3 mnPCE/1,000. Eighty-six percent of the most commonly used mouse stocks have historical mean frequencies within this range. Though individual experimental mean values would not necessarily be expected to fall within the 1-3.00 mnPCE/1,000 range, 65.3% of the 2,327 published negative control values do, and 83.5% are < 3 mnPCE/1,000. The frequency with which an individual experimental mean value lies outside the 1.00 to 3.00 mnPCE/1,000 range differs among stocks and appears related to the mouse mean frequency. We suggest that the recommended range for historical mean frequency be extended slightly, to approximately 3.4 mnPCE/1,000, to accommodate some commonly used strains with overall mean negative control frequencies just above 3.00 mnPCE/1,000.(ABSTRACT TRUNCATED AT 400 WORDS)
Environ Mol Mutagen 1994
PMID:Bone marrow micronucleus assay: a review of the mouse stocks used and their published mean spontaneous micronucleus frequencies. 801 72

Regulatory sequences and nuclear factors governing tissue-restricted expression of the mouse arrestin gene were investigated. The results showed that while proximal promoter sequence positions -38 to +304 are sufficient to direct low levels of retina-specific gene expression, sequences extending upstream to position -209 support higher levels of expression in the retina, as well as detectable expression in the lens, pineal gland, and brain. Within the interval between positions -209 and -38, a broadly expressed nuclear factor, Bd, binds to sequences centered between positions -205 and -185, a region which contains two direct repeats of the hexamer, TGACCT. The proximal promoter binds three apparently retina-specific nuclear factors, Bp1, Bp2, and Bp3, through overlapping sequences centered between positions -25 and -15. Bp1 and Bp3 also recognize a closely related sequence found in the promoter regions of several other vertebrate photoreceptor-specific genes. Moreover, the consensus binding site for Bp1, designated PCE I, is identical to RCS I, an element known to play a critical role eliciting photoreceptor-specific gene expression in Drosophila melanogaster. The results suggest that PCE I and RCS I are functionally as well as structurally similar and that, despite marked differences in the fly and vertebrate visual systems, the transcriptional machinery involved in photoreceptor-specific gene expression has been strongly evolutionarily conserved.
Mol Cell Biol 1993 Jul
PMID:The proximal promoter of the mouse arrestin gene directs gene expression in photoreceptor cells and contains an evolutionarily conserved retinal factor-binding site. 832 Dec 39

The effect of conditioning pretreatment with 0.025 Gy of gamma rays on micronucleated polychromatic erythrocyte (MN-PCE) induction by 1.0 or 0.1 Gy of gamma rays was determined in murine peripheral blood. The adaptive and challenge doses as well as the timing of their administration were taken from a previously reported experiment [Farooqi and Kesavan (1992). Mutat Res 302:83-89]. The response was determined by the strategy of measuring the area below the curve (ABC) of MN-PCE induction vs. time. This strategy permits one to determine an index of total damage and to establish if conditioning exposure affects the timing of MN-PCE appearance in the blood stream, which in turn could cause an apparent difference in response between the conditioned and the unconditioned groups at specific times. The results indicate that low dose gamma ray pretreatment does not protect against MN-PCE induction by the challenge gamma ray dose, and that there was no change on the kinetics of MN-PCE appearance in peripheral blood.
Environ Mol Mutagen 1997
PMID:No radioadaptive response to micronucleated polychromatic erythrocyte (MN-PCE) induction in murine peripheral blood in vivo. 914 72

Phenolphthalein, a common ingredient in nonprescription laxatives and a multisex, multispecies rodent carcinogen, was evaluated under chronic exposure conditions for genotoxicity in transgenic female mice heterozygous for the p53 gene (heterozygous TSG-p53 mice). Phenolphthalein was administered in the diet at 200, 375, 750, 3,000, and 12,000 ppm (corresponding to a time-weighted average of 37, 71, 146, 569, and 2,074 mg/kg/day, respectively) for 6 months (183 days). On days 39, 92, 137, and 183 of treatment, peripheral blood samples were collected and evaluated for the frequency of micronucleated polychromatic and normochromatic erythrocytes (MN-PCE and MN-NCE, respectively), the percentage of PCE (%PCE) among total erythrocytes, and the extent of DNA damage (single strand breaks, alkali labile sites, DNA crosslinking) in leukocytes. In addition, the extent of DNA damage was evaluated in liver parenchymal cells sampled from mice at the end of the 6-month treatment period. DNA damage was evaluated using the alkaline (pH > 13) Single Cell Gel (SCG) assay. In addition, using a modified SCG technique, the frequencies of leukocytes and liver parenchymal cells with extremely low molecular weight DNA (indicative of apoptosis and/or necrosis) were determined. At each sample time, phenolphthalein induced a highly significant, dose-dependent increase in the frequency of MN-PCE and MN-NCE and in %PCE. Maximal induction of MN-PCE and %PCE decreased with increasing treatment duration, most likely due to a treatment duration-dependent decrease in the relative amount of ingested phenolphthalein. A comparative analysis of the kinetochore status of MN in erythrocytes sampled from control mice and mice ingesting phenolphthalein at 12,000 ppm for 183 days indicates that the induced MN resulted predominantly but not exclusively from numerical chromosomal damage. The analysis for increased levels of DNA damage in blood leukocytes was inconclusive, with a small but statistically significant increase in DNA migration on days 39 and 137 but not on days 92 and 183. The extent of DNA migration in liver parenchymal cells sampled from mice at the end of treatment was not altered significantly. The frequencies of apoptotic and/or necrotic leukocytes and liver parenchymal cells were not increased among mice ingesting phenolphthalein. The lowest effective dose at which a significant genotoxic response (i.e., the induction of MN-NCE) was detected was 200 ppm, the lowest dose tested in this study. This dose in mice is comparable to doses (on a mg/m2 basis) experienced by humans.
Environ Mol Mutagen 1998
PMID:Measurement of micronucleated erythrocytes and DNA damage during chronic ingestion of phenolphthalein in transgenic female mice heterozygous for the p53 gene. 954 89

Peromyscus leucopus (white-footed mouse) and Cryptotis parva (least shrew) possess desirable attributes for biomonitoring contamination of terrestrial ecosystems, but few studies have examined the potential use of these species for monitoring exposure to genotoxic contaminants. The susceptibility of laboratory-reared C. parva, P. leucopus, and Mus musculus (house mouse, strain CD-1) to micronucleus (MN) induction by known clastogens was evaluated. Animals were exposed for 24 hr to methyl methanesulfonate (MMS; 12.5, 25, and 50 mg/kg), 4-nitroquinoline 1-oxide (4-NQO; 7.5, 15, and 30 mg/kg), or mercuric chloride (HgCl2; 6, 12, and 24 mg/kg). Both MMS and 4-NQO induced dose-related increases in micronucleated polychromatic erythrocytes (MNPCE) in all three species, whereas HgCl2 induced a weak response only in P. leucopus. P. leucopus and C. parva were more sensitive than M. musculus to MMS. Similar micronucleus responses to 4-NQO were seen in each of the species. The feasibility of using blood for MN assessment was evaluated by comparing MN frequencies in bone marrow (BM) PCE, and blood PCE and normochromatic erythrocytes (NCE) in untreated animals, and following daily treatment for 1, 2, 3, and 10 days with 0.4 mg/kg triethylenemelamine (TEM). The results indicated that micronucleated erythrocytes were removed from the circulating blood in P. leucopus, but not in C. parva. Measurement of BM and blood MN levels appears feasible for monitoring exposure to genotoxic agents in C. parva and P. leucopus, and for distinguishing between acute and chronic exposure in C. parva.
Environ Mol Mutagen 1999
PMID:Feasibility of micronucleus methods for monitoring genetic damage in two feral species of small mammals. 1033 24

Pregnyl (hCG), a preparation of human chorionic gonadotropin, was evaluated for its effects on the endocrinological, biochemical and genotoxic changes in female Swiss albino mice. hCG treatment at different doses (25, 50 and 100 I.U./Kg/day) for 5 days was found to significantly increase the plasma levels of hCG, estradiol and progesterone in a dose-dependent manner, while the concentrations of LH and FSH remained below the detection levels. The plasma levels of ALT, CK-MB, creatinine and urea were significantly decreased, whereas the concentrations of AST were significantly increased. The treatment was found to significantly increase and decrease the hepatic concentrations of MDA and NP-SH respectively. The hepatic levels of proteins and DNA were not affected, but there was a significant increase in the concentrations of RNA. In addition, hCG treatment did not show any effect on the frequency of occurrence of micronuclei, whereas the ratio of PCE/NCE was found to be significantly increased. These results demonstrate that the hCG treatment in mice affected the pituitary-ovarian hormones in a similar pattern to that of humans. The treatment increased oxidative stress in hepatic cells without disturbing the functions of the liver as well as other organs. This finding may be of value concerning the safe use of hCG and may contribute to the overall antioxidant balance in the body.
Res Commun Mol Pathol Pharmacol 1999
PMID:Evaluation of the effects of pregnyl on pituitary-ovarian hormones and biochemical markers of tissue injury in female Swiss albino mice. 1085 Mar 79

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that induces Parkinsonism in humans, monkeys, and mice and oxidative stress in mammalian cells and tissues. In the present study, the relationship between the generation of lipid peroxidation products and DNA damage was studied in mice treated with MPTP. The frequency of micronucleated polychromatic erythrocytes (MN-PCE) and the concentrations of malonaldehyde and 4-hydroxyalkenals were determined in the bone marrow and peripheral blood of mice 0, 24, 48, 72, and 96 hr after treatment with MPTP, cyclophosphamide as a positive control, or diluent. Both MN-PCE and the lipid peroxidation products increased in MPTP-treated mice, with significant levels being detected in bone marrow starting at 24 hr after treatment and in blood starting at 48 hr after treatment. These results suggest that the generation of oxidative products is related to the DNA damage produced by MPTP in mice.
Environ Mol Mutagen 2003
PMID:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced lipid peroxidation and DNA damage in mouse bone marrow and blood. 1255 93

Liv 52 is a mixture of botanicals that is used clinically to treat various hepatic disorders. In this study, the radioprotective activity of Liv 52 was evaluated in mice given whole-body exposure to different doses of gamma-radiation. In addition, a series of studies was conducted to explore the mechanism of radioprotection. Radioprotection was evaluated by the ability of Liv 52 to reduce both the frequency of bone marrow micronucleated erythrocytes and the lethality produced by (60)Co gamma-radiation. Mice were treated by oral gavage once daily for seven consecutive days with 500 mg/kg body weight Liv 52 or carboxymethylcellulose vehicle prior to radiation. Micronucleated polychromatic erythrocytes (MPCEs), micronucleated normochromatic erythrocytes (MNCEs), and the PCE/NCE ratio were measured at 0.25-14 days after exposure to whole-body radiation doses of 0, 0.5, 1.5, 3.0, or 4.5 Gy; animal survival was monitored after doses of 7, 8, 9, 10, 11, or 12 Gy. Pretreatment of mice with Liv 52 significantly reduced the frequency of radiation-induced MPCEs and MNCEs. Irradiation reduced the PCE/NCE ratio in a dose-related manner for up to 7 days following irradiation; Liv 52 pretreatment significantly mitigated against these reductions. Liv 52 treatment also reduced the symptoms of radiation sickness and increased mouse survival 10 and 30 days after irradiation. Liv 52 pretreatment elevated the levels of reduced glutathione (GSH), increased the activities of glutathione transferase, GSH peroxidase, GSH reductase, superoxide dismutase, and catalase, and lowered lipid peroxidation (LPx) and the activities of alanine amino transferase and aspartate aminotransferase 30 min after exposure to 7 Gy of gamma-radiation. Liv 52 pretreatment also reduced radiation-induced LPx and increased GSH concentration 31 days following the exposure. The results of this study indicate that pretreatment with Liv 52 reduces the genotoxic and lethal effects of gamma-irradiation in mice and suggest that this radioprotection may be afforded by reducing the toxic effects of the oxidative products of irradiation.
Environ Mol Mutagen 2006 Aug
PMID:Evaluation of the radioprotective effect of Liv 52 in mice. 1675 71

Micronucleated reticulocyte (MN-RET) scoring by flow cytometry (FCM) has been used in assessment of the clastogenic effects of chemicals. However, its dose-response to acute whole body irradiation (WBI) at moderate dose rates remains to be established. We show that FCM scoring of MN-RET in peripheral blood from male ICR mice exposed to WBI X-ray doses of 0.5-5 Gy at a dose rate of 0.488 Gy/min exhibits a linear dose-response relationship 24, 48, and 72 hr following WBI. Parallel microscopic counting of micronucleated polychromatic erythrocytes (MN-PCE) in bone marrow smears from the same animals showed similar linear dose-response patterns at the same time points. Indeed, MN-RET and MN-PCE were highly correlated at all doses and time points. In view of the speed and accuracy of this method, in addition to the small blood sample size needed for the assay, the flow cytometric protocol for MN-RET scoring may provide a minimally-invasive, high throughput radiation biodosimeter.
Environ Mol Mutagen 2010 Apr
PMID:Flow cytometric scoring of micronucleated reticulocytes as a possible high-throughput radiation biodosimeter. 1979 Feb 59


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