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Query: UNIPROT:P06889 (Mol)
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Incubation of whole mouse brain homogenate with [3H]progesterone resulted in two metabolites: the 5 alpha-reduced product, 5 alpha-pregnane-3,20-dione and another metabolite at a 3-fold greater yield. This differed from rat brain, which produced predominantly the 5 alpha-reduced metabolite under the same conditions. Subcellular fractionation of mouse brain demonstrated a particulate location for the 5 alpha-reduction of progesterone and a cytosolic location for the production of the unknown major metabolite. Treatment of this unknown metabolite with chromium trioxide resulted in a reconversion to progesterone, indicating the presence of a hydroxyl at position 3 or 20. Comparison of the chromatographic behaviour of the unknown metabolite with that of authentic progesterone derivatives suggested that this metabolite corresponds to 20-hydroxy-4-pregnene-3-one.
J Steroid Biochem Mol Biol 1994 Aug
PMID:Metabolism of progesterone in mouse brain. 804 52

Previous studies have shown that a number of different genotoxic carcinogens that induce different types of DNA damage preferentially alter the expression of inducible genes in vivo. To investigate further the mechanistic basis for these effects, we examined the effects of the human lung carcinogen chromium(VI) on expression of the hormone-inducible cytosolic phosphoenolpyruvate carboxykinase (PEPCK) gene in chick embryo liver. Chromium(VI) pretreatment had significant effects on both basal and glucocorticoid-inducible PEPCK expression in 14-d-old embryo liver. These effects were principally a result of changes in PEPCK transcription. In contrast, treatment with chromium(VI) 1 h after treatment with glucocorticoid had no effect on PEPCK induction, suggesting that an early event in the induction process is the target for carcinogen effects. In 16-d-old liver, in which PEPCK expression is no longer responsive to glucocorticoid induction, both basal and inducible PEPCK expression were also refractory to chromium(VI) effects, indicating that carcinogen responsiveness is a phenotypic rather than an inherent property of inducible genes and is related to their competence for induction. Chromium(VI) had no effect on cAMP induction of PEPCK expression, demonstrating that carcinogens target their effects to specific regulatory pathways. Comparison of the effects of chromium(VI) with those of cycloheximide suggests that chromium(VI) targets its effects to a labile, constitutively expressed repressor involved in PEPCK gene regulation.
Mol Carcinog 1994 Aug
PMID:Effects of the genotoxic carcinogen chromium(VI) on basal and hormone-inducible phosphoenolpyruvate carboxykinase gene expression in vivo: correlation with glucocorticoid- and developmentally regulated expression. 806 79

Very little is known about the structural composition of the restenotic plaque in evolution. The responses of atherosclerotic femoral arteries of rabbits to balloon angioplasty (BA), thallium/holmium/chromium: YAG infrared laser angioplasty (LA), combined LA and BA, or no angioplasty were compared by blinded quantitative histomorphometry and angiography. The endothelium was injured by nitrogen/air desiccation, and the animals were fed a 2% cholesterol diet for 1 month prior to the angioplasty procedure. Animals were sacrificed 2 hr or 28 days after angioplasty by pressure perfusion with 10% formaldehyde (100 mm Hg), and arterial segments (4-5 cm) were excised bilaterally. The frequency of thrombus was greatest in arteries with LA. Arteries with combined LA and BA had the greatest initial gain in luminal diameter by angiography, but they also had the greatest reduction in luminal diameter from 2 hr to 28 days and the greatest cross-sectional area narrowing by plaque at 28 days. The principal component of the intimal plaques in all groups was fibrous tissue (approximately 90%), with the remainder consisting primarily of "foam cells." By multiple regression analysis, the strongest predictors of cross-sectional area narrowing were contiguity of foam cells between the intima and media, depth of the tear, percentage of foam cells in the plaque, and the intervention of LA followed by BA. The principal predictors of foam cells in the plaque, irrespective of treatment, were also cross-sectional area narrowing, contiguity of foam cells between plaque and media, and the depth of tear. It is suggested that a large proportion of the foam cells of the intima may be derived from foam cells of the media and adventitia rather than from the lumen. These observations may be of particular importance regarding angioplasty in young people where foam cells occupy a significantly greater proportion of the atherosclerotic plaque.
Exp Mol Pathol 1993 Dec
PMID:Response of femoral arteries of cholesterol-fed rabbits to balloon angioplasty with or without laser: emphasis on the distribution of foam cells. 813 4

Carcinogenic chromium (Cr6+) enters cells via the sulfate transport system and undergoes intracellular reduction to trivalent chromium, which strongly adducts to DNA. In this study, the effect of adducted trivalent chromium on in vitro DNA synthesis was analyzed with a polymerase-arrest assay in which prematurely terminated replication products were separated on a DNA sequencing gel. A synthetic DNA replication template was treated with increasing concentrations of chromium(III) chloride. The two lowest chromium doses used resulted in biologically relevant adduct levels (6 and 21 adducts per 1,000 DNA nucleotides) comparable with those measured in nuclear matrix DNA from cells treated with a 50% cytotoxic dose of sodium chromate in vivo. In vitro replication of the chromium-treated template DNA using the Sequenase version 2.0 T7 DNA polymerase (United States Biochemical Corp., Cleveland, OH) resulted in dose-dependent polymerase arrest beginning at the lowest adduct levels analyzed. The pattern of polymerase arrest remained consistent as chromium adduct levels increased, with the most intense arrest sites occurring 1 base upstream of guanine residues on the template strand. Replication by the DNA polymerase I large (Klenow) fragment as well as by unmodified T7 DNA polymerase also resulted in similar chromium-induced polymerase arrest. Interstrand cross-linking between complementary strands was detected in template DNA containing 62, 111, and 223 chromium adducts per 1,000 DNA nucleotides but not in template containing 6 or 21 adducts per 1,000 DNA nucleotides, in which arrest nevertheless did occur. Low-level, dose-dependent interstrand cross-linking between primer and template DNA, however, was detectable even at the lowest chromium dose analyzed. Since only 9% of chromium adducts resulted in polymerase arrest in this system, we hypothesized that arrest occurred when the enzyme encountered chromium-mediated interstrand DNA-DNA cross-links between either the template and a separate DNA molecule or the template and its complementary strand in the same molecule. These results suggest that the obstruction of DNA replication by chromium-mediated DNA-DNA cross-links is a potential mechanism of chromium-induced genotoxicity in vivo.
Mol Carcinog 1994 Mar
PMID:DNA polymerase arrest by adducted trivalent chromium. 814 16

A groups of six chemical compounds was tested in parallel in two different somatic genotoxicity assays in Drosophila melanogaster, the wing somatic mutation and recombination test (SMART) and the white-ivory eye spot test. The wing spot test makes use of the wing cell markers multiple wing hairs (mwh) and flare (flr) and detects both mitotic recombination and various types of mutational events. The white-ivory eye spot test makes use of the white-ivory (wi) quadruplication and detects the somatic reversion of the recessive eye color mutation wi to the wild-type (w+). Three- or two-day-old larvae were fed chronically with the compounds ethylnitrosourea (ENU), N-nitrosopyrrolidine (NNP), caffeine (CAF), chromium (VI) oxide (CRO), potassium chromate (POC), and 2,4-dichlorophenoxyacetic acid (2,4-D). All six compounds are genotoxic to various degrees in the wing spot test. The percentage of the genotoxic activity that is due to mitotic recombination was between 84% and 91% for the hexavalent chromium compounds CRO and POC and about 68% for 2,4-D. In contrast, ENU and NNP showed only 46% and 25% recombinagenic activity, respectively. In the white-ivory eye spot test, the three compounds (CRO, POC, and 2,4-D) with high recombinagenic activity and CAF were clearly nongenotoxic, whereas only ENU and NNP gave a positive response. From these results, it is concluded that the spectrum of genotoxic events detected by the two assays is different. In particular, the white-ivory eye spot test appears not to detect mitotic recombination the way the wing spot test does.
Environ Mol Mutagen 1996
PMID:The somatic white-ivory eye spot test does not detect the same spectrum of genotoxic events as the wing somatic mutation and recombination test in Drosophila melanogaster. 862 58

The role of the lysosome during the intracellular concentration of diverse mineral elements has been evidenced by the electron probe X-ray microanalysis (EPMA). This highly sensitive technique allows an in situ chemical analysis of any chemical element with an atomic number greater than 11, present in ultra-thin tissue sections. Therefore, it has been demonstrated by using this EPMA that 21 out of the 92 elements of the periodic table, once injected in a soluble form, were selectively concentrated within lysosomes of several types of mammalian cells. Amongst these 21 elements, 15 are concentrated and precipitated in an insoluble from in association with phosphorus whereas the other 6 are precipitated in association with sulphur. Amongst the 15 elements which precipitate with phosphorus in lysosomes, there are: 3 group IIIB elements of the periodic system, (aluminium, gallium and indium); the rare-earth elements (cerium, gadolinium, lanthanum, thulium and samarium); 2 group IVA elements (hafnium and zirconium), two actinides (uranium and thorium) and elements such as chromium and niobium. The 6 elements which precipitate with sulphur comprise the 3 group VIII elements of the classification (nickel, palladium, platinum) and the 3 group IB elements (copper, silver and gold). The mechanisms responsible for this selective concentration involve enzymatic processes and predominantly acid phosphatases for elements precipitating as phosphates and arylsulfatases for elements precipitating with sulphur.
Cell Mol Biol (Noisy-le-grand) 1996 May
PMID:The role of lysosomes in the selective concentration of mineral elements. A microanalytical study. 879 93

Certain chromium (Cr) compounds are known to be carcinogenic in humans and mutagenic in cell culture. However, the mechanism of Cr mutagenesis is not well understood. It appears that intracellular reduction of Cr by agents such as glutathione plays a role in the induction of DNA damage. We have used a simian virus 40-based shuttle vector to investigate the relationship between chromium-induced DNA damage and Cr mutagenicity. The treatment of the plasmid pZ189 with Cr(VI) plus glutathione (GSH) induced DNA strand breaks and reduced the plasmid biological activity, whereas Cr(III) treatment with or without GSH did not give rise to such DNA damage. When Cr(VI)/GSH- or Cr(III)/GSH-treated pZ189 was replicated in mammalian cells, a dose-dependent increase in mutant frequency was observed with Cr(VI)/GSH-treated pZ189, but not with Cr(III)/GSH-treated plasmid. About 43% of the mutants from Cr(VI)/GSH-treated pZ189 were deletion mutants. The remainder were base substitution mutants, mostly GC-->AT transitions and GC-->TA transversions. This pattern of mutagenesis is similar to that observed with other agents that cause oxidative DNA damage such as ionizing radiation and H2O2. These results support the hypothesis that Cr mutagenesis can be induced by the generation of reactive oxygen intermediates during the reduction of Cr(VI) by glutathione.
Environ Mol Mutagen 1996
PMID:Induction of mutagenic DNA damage by chromium (VI) and glutathione. 884 87

Dietary consumption of green vegetables has been associated with protection against mutagenic and clastogenic activity of genotoxicants. Chlorophyll, being present in all green plants, had earlier been suggested to be the principal factor involved. Mice were administered (i) crude aqueous extract of leaf of Indian spinach, Beta vulgaris L. var.benghalensis Hort., and equivalent amounts of (ii) chlorophyll extracted from the leaf; (iii) purified chlorophyll, (iv) chlorophyllin, a sodium-copper derivative of chlorophyll; daily for 7 days. On day 7, one set of mice from each treatment was administered potassium dichromate-a known metallic clastogen. The mice were sacrificed after 24 hours. Chromosome preparations were made from bone marrow following the usual colchicine-air dry-Giemsa schedule. The cytogenetic endpoints scored were chromosomal aberrations and damaged cells. Crude leaf extract and chlorophyllin were nonclastogenic and reduced the clastogenic effects of potassium dichromate to the control distilled water level. Chlorophyll alone, whether extracted from the leaf or obtained in commercially purified form, was clastogenic and could reduce the effects of the chromium salt only to its own level. The protective action of the crude leaf extract may be attributed to the total effect of the interaction between the different components within the leaf extract, in which the clastogenicity of chlorophyll had been neutralized.
Environ Mol Mutagen 1996
PMID:Clastogenic activity of pure chlorophyll and anticlastogenic effects of equivalent amounts of crude extract of Indian spinach leaf and chlorophyllin following dietary supplementation to mice. 884 93

Heme oxygenase catalyzes the first and rate-controlling step in heme catabolism. One of the two forms of heme oxygenase (heme oxygenase-1) has been shown to be increased by heme, metals, and in some systems, by certain environmental stresses. However, it remains uncertain whether heme induces hepatic heme oxygenase-1 by a general stress response, or a specific heme-dependent cellular response. The work communicated here explores this issue by examining possible mechanisms whereby heme and other metalloporphyrins induce heme oxygenase-1 in normal liver cells. Primary cultures of chick embryo liver cells were tested for their ability to increase heme oxygenase mRNA after exposure to selected metalloporphyrins (heme, chromium mesoporphyrin, cobalt protoporphyrin and manganese protoporphyrin). The ability of antioxidants to decrease metalloporphyrin-mediated induction of heme oxygenase-1 mRNA was also tested. Our results indicate that: 1) the increase in heme oxygenase-1 mRNA mediated by heme or other metalloporphyrins may involve a short-lived protein(s) since the increase was prevented by several inhibitors of protein synthesis; and 2) in normal liver cells, heme-dependent oxidative stress does not play a key role in the heme-mediated induction of heme oxygenase-1. We conclude that heme and other non-heme metalloporphyrins induce heme oxygenase-1 through a mechanism requiring protein synthesis, not because metalloporphyrins increase cellular oxidative or other stress.
Mol Cell Biochem 1997 Apr
PMID:Mechanism of induction of heme oxygenase by metalloporphyrins in primary chick embryo liver cells: evidence against a stress-mediated response. 908 26

We investigated the role of endogenous or exogenous nitric oxide (NO) on human lymphocyte function. We used sodium nitroprusside, nitroglycerine, S-nitroso-N-acetylpenicillamine, sodium nitrite and S-nitroso-L-glutathione as NO-generating compounds. All agents were used at doses that do not produce direct cytotoxicity as measured by trypan blue exclusion as well as chromium-51 release assay. The immune responses examined were peripheral blood lymphocytes (PBL) proliferation and IL-2 production after activation with OKT3 and PHA; allogeneic mediated proliferation and cell mediated cytotoxicity (CML) in MLR; IgG and IgM production after PBL activation with Con-A; proliferation and expression of IFN-gamma and IL-4 mRNA after activation of allogeneic CD4+T cell clones. Cytokine mRNA expression was measured by reverse transcriptase PCR. Our results show that proliferating lymphocytes do not produce a detectable amount of NO as measured by the Griess reaction. In separate experiments, the addition of NG-monomethyl-L-arginine (L-NMMA) did not affect lymphocyte proliferation. Sodium nitroprusside and nitroglycerine exerted a dose dependent antimitogenic effect, inhibited cytokine production and expression, CML generation and antibody production. DNA gel electrophoresis showed no evidence for enhanced programmed cell death. The antimitogenic effect could not be blocked by the NO scavengers, hemoglobin or methylene blue. In contrast, the other nitric oxide generating compounds did not inhibit lymphocyte mitogenesis. The results suggest that human lymphocytes do not produce appreciable amounts of NO to affect lymphocyte mitogenesis. Sodium nitroprusside and nitroglycerine have a potent but nonspecific immunoinhibitory effect on human lymphocyte function by a mechanism other than NO production. In addition, pharmacological levels of NO do not inhibit human lymphocyte mitogenesis.
Mol Cell Biochem 1997 Jun
PMID:Analysis of the in vitro effect of exogenous nitric oxide on human lymphocytes. 920 99


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