Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diethyldithiocarbamic-acid-methyl ester (DDTC-Me) is a major metabolite of disulfiram. When given to rats, DDTC-Me was found to inhibit the liver mitochondrial low Km aldehyde dehydrogenase (ALDH) without having any effect on the high Km isoenzyme. Inhibition of low Km ALDH by DDTC-Me in vivo exhibited a dose-response relationship, with inhibition of ALDH from 11% to 90% found when DDTC-Me was administered in a dose range from 1.8 to 158 mg/kg, IP. After a single dose of DDTC-Me (41.2 mg/kg, IP), the low Km ALDH was inhibited for 168 hours suggesting an irreversible enzyme inhibition. After an ethanol challenge to DDTC-Me-treated rats, a decrease in mean arterial pressure (MAP) and increase in heart rate was observed. Decreases in MAP occurred almost immediately after ethanol challenge and remained low throughout a four hour post-ethanol period. These results suggest that in vivo administration of DDTC-Me can cause an alcohol-sensitizing reaction, and that DDTC-Me actually may be the metabolite of disulfiram which produces the disulfiram-ethanol reaction. It is proposed the reaction be more correctly identified as the DDTC-Me-Ethanol Reaction or D-MER.
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PMID:Diethyldithiocarbamic acid-methyl ester: a metabolite of disulfiram and its alcohol sensitizing properties in the disulfiram-ethanol reaction. 282 42

The formation of methylthio metabolites of epoxides has been shown to be a significant route of metabolism in some species. Several aspects of this metabolic conversion for indene were examined. Two isomers of hydroxy(methylthio)indane were found in the urine of guinea pigs administered indene (14.3 and 100 mg/kg, ip). The major isomer, 2-hydroxy-1-methylthioindane (I) was present as 6-9% of the administered dose after 24 hr, while lower amounts (0-0.6%) of a minor isomer (II) were observed. A significant amount of isomer I was found as a urinary metabolite of indene oxide (14% of 12.5 mg/kg, ip). To further elucidate the route of formation of I, the glutathione (I-GLU) and mercapturic acid (I-MER) conjugates of indene oxide were synthesized and administered to the guinea pig. The methylthio metabolite I was present as a significant urinary metabolite of both conjugates of indene oxide, comprising 9.6% and 5.7% of the dose of I-GLU (5 mg, ip) and I-MER (4 mg, ip), respectively. These results show that the formation of a hydroxy(methylthio)indane is a significant route of metabolism for indene and indene oxide in the guinea pig, and that this metabolite arises via further metabolism of conjugates in the glutathione pathway. In the rat, isomer I is a minor metabolite. Mechanistic aspects of the formation of these thioether metabolites are discussed.
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PMID:Formation of methylthio metabolites of indene in the guinea pig and the rat. 286 72

We determined whether the reduction in placental progesterone (P4) production observed after administration of the antiestrogen ethamoxytriphetol (MER-25) to pregnant baboons was associated with a decline in activity and/or content of the placental mitochondrial cholesterol side-chain cleavage system (P-450scc). Pregnant baboons (Papio anubis) were untreated (n = 9) or administered MER-25 (25 mg/kg BW, orally; n = 6) daily on days 140-170 of gestation (term = 184 days). Placentas were obtained by cesarean section on day 170 of gestation, and P-450scc activity and cytochrome P-450 content were determined on mitochondria-rich fractions. Administration of MER-25 to pregnant baboons resulted in a 40% reduction (P less than 0.01, by Student's t test) in the mean (+/- SE) peripheral serum P4 concentration (6.3 +/- 0.3 ng/ml) compared to that in untreated (10.4 +/- 0.3 ng/ml) baboons. P-450scc activity, as determined by formation of pregnenolone (P5) and P4 during a 30-min incubation (picomoles per mg protein), was 37% lower (P less than 0.01) in placental mitochondria obtained from MER-25-treated baboons (179.8 +/- 25.0) than in that from untreated (285.4 +/- 13.4) baboons. Mitochondrial cytochrome P-450 content, assessed by spectral analysis, was 28% lower (P less than 0.02) in antiestrogen-treated (46.7 +/- 2.1 pmol/mg protein) than in untreated (64.8 +/- 5.2 pmol/mg protein) baboons. The initial (time zero) free cholesterol content (nanomoles per mg protein) of mitochondrial-rich preparations was not significantly different in antiestrogen-treated (189.3 +/- 13.0) and untreated (225.0 +/- 15.1) animals. Collectively, these results suggest that the decline in placental P4 production observed in baboons in response to MER-25 occurs at least in part as a result of a decrease in cytochrome P-450scc activity. The loss in P-450scc activity appears to be an intramitochondrial event and not a result of depletion of the total mitochondrial cholesterol pool. We propose, therefore, that one mechanism by which estrogen may regulate the production of P4 by the placenta during primate pregnancy is via the maintenance of placental mitochondrial cytochrome P-450, the terminal oxidase of cytochrome P-450scc.
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PMID:Regulation of progesterone biosynthesis by estrogen during baboon pregnancy: placental mitochondrial cholesterol side-chain cleavage activity in antiestrogen (ethamoxytriphetol, MER-25)-treated baboons. 292 16

In the present study, a culture system of human placental cells was established to examine the role of estrogen and androgen in progesterone (P4) formation. Normal human placentae were obtained at term, and cells were dispersed in Hank's Balanced Salt Solution (5 ml/g tissue) containing 0.1% collagenase, 0.1% hyaluronidase, 0.01% deoxyribonuclease, and 1% fetal bovine serum for 2 h at 37 C. Dispersed placental cells (10(6) cells/ml) were placed in medium 199 with modified Earle's salts (pH 7.4) containing 10% fetal bovine serum, 12.5 mM HEPES buffer, 26 mM NaHCO3, and 40 micrograms/ml Gentamycin-SO4 and incubated for 72 h at 37 C and 5% CO2 in air to allow cell attachment. Medium was then changed (time zero), and P4 formation was studied thereafter. Culture of placental cells for 96 h resulted in linear increases in P4 and estradiol (E2) formation, indicating the maintenance of cell viability and steroidogenic function. Mean +/- SE P4 formation at 48 h was 246 +/- 16 pg/micrograms DNA. To assess the role of estrogen on P4 formation, placental cells were incubated for a period of 48 h with various amounts (10(-7)-10(-4)M) of the antiestrogen ethamoxytriphetol (MER-25), the aromatase inhibitor 4-hydroxyandrostenedione (4-OHA), and/or E2. Both MER-25 and 4-OHA resulted in a dose-dependent decline (P less than 0.01) in P4 formation (greater than 80% decline at 10(-4)M MER-25 or 4-OHA). The marked reduction in P4 formation caused by 4-OHA alone was reversed by concomitant addition of E2; however, E2 alone had no effect. To assess the role of androgens on P4 formation, cells were incubated for 48 h with increasing amounts (10(-7)-10(-4)M) of androstenedione, dehydroepiandrosterone (DHA), or dihydrotestosterone. Although the formation of E2 was enhanced by DHA, formation of P4 was not affected by the aromatizable androgens DHA or androstenedione or the nonaromatizable dihydrotestosterone. The decline in P4 formation by human placental cells in culture elicited by MER-25 or 4-OHA supports the hypothesis of a regulatory role for estrogen in placental P4 formation during human pregnancy. The lack of effect of exogenous estrogen suggests that the action of estrogen on P4 formation may be permissive.
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PMID:Regulation of progesterone formation by human placental cells in culture. 294 94

The effect of polyenoic phospholipids on the concentration of serum lipids and the activity of lecithin cholesterol acyltransferase (LCAT, E.C. 2.3.1.43) was investigated in 18 patients with chronic glomerulonephritis accompanied by hyperlipaemia and reduced rate of cholesterol esterification in the plasma. The effects of therapy were evaluated immediately after a 2-month period of treatment and again after a 3-month drug free interval following termination of the therapy. An immediate effect of the treatment was reflected in a significant increase in the fractional esterification rate (FER % .h-1) and a marked reduction of the concentration of triglycerides (TG). Discontinuation of the drug resulted in the return of TG and FER values to the initial levels and in a rise of total (TCH) and unesterified cholesterol (UCH), HDL-cholesterol (HDL-TCH) and the molar esterification rate (MER mumol.1-1.h-1). The activity of LCAT estimated by radioassay in common and endogenous substrates varied in parallel.
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PMID:Effect of polyenoic phospholipid therapy on lecithin cholesterol acyltransferase activity in the human serum. 297 6

Patients with limited-stage small-cell carcinoma of the lung (SCCL) were randomly assigned to a four-drug chemotherapy program consisting of methotrexate, doxorubicin, cyclophosphamide, and CCNU (MACC) or to a regimen consisting of cyclophosphamide, CCNU, and vincristine alternated with Adriamycin (Adria Laboratories, Columbus, Ohio) and vincristine (CCV/AV). All patients received 4,500 cGy, in a split course, to the primary tumor, mediastinum, and supraclavicular lymph node drainage areas and 3,000 cGy to the whole brain. After four cycles of chemotherapy, patients were randomly assigned to chemotherapy plus methanol extractable residue of BCG (MER-BCG) or no MER-BCG. The complete response frequencies were similar for the two regimens (54% and 48%) as were the median survivals (12.0 and 11.5 months) and the two-year survival rates (15% and 17%). Immunotherapy with MER-BCG did not prolong the time to disease progression or improve survival. Women had a greater chance of achieving a complete remission independent of performance status. There was a complex interaction between sex and the chemotherapy regimens that may have important implications for the design and stratification of future trials in SCCL.
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PMID:Combined modality therapy with radiotherapy, chemotherapy, and immunotherapy in limited small-cell carcinoma of the lung: a Phase III cancer and Leukemia Group B Study. 299 78

Transformation of Pseudomonas putida and analysis for plasmid DNA revealed that both n-alkane oxidation and mercury resistance are encoded on a single 220-megadalton OCT plasmid molecule. Derivatives of OCT having lost the mercury resistance function could be readily isolated and contained a smaller plasmid estimated to be 170 megadaltons. The results show that segregation of the mercury resistance property occurs not by loss of a separate MER plasmid as previously thought but by a deletion in the OCT plasmid.
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PMID:Characterization of the OCT plasmid encoding alkane oxidation and mercury resistance in Pseudomonas putida. 300 35

The present study was designed to study the effect of dietary fat intake on the modulation of dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis in rats injected with the methanol extract residue of Bacillus Calmette-Guerin (MER-BCG). Rats were maintained on either a 5% or a 20% corn oil diet for the entire duration of the experiment. When MER-BCG was administered 2 and 3 weeks before DMBA, mammary tumorigenesis was suppressed in the 2 dietary groups with different levels of fat intake. This was in contrast to when MER-BCG was administered 3 and 5 weeks after DMBA; in this case the development of mammary tumors was noticeably enhanced regardless of the fat intake of the host. The magnitude of inhibition or increase by MER-BCG was similar in animals fed either fat level, although a high fat diet consistently stimulated mammary tumorigenesis in the 2 experiments. In vitro assays on T cell mitogen-induced blastogenesis and natural killer cell activity in splenocytes isolated from the untreated rats showed that dietary fat failed to elicit any differential response in these immune functions.
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PMID:BCG-modulated mammary carcinogenesis is dependent on the schedule of immunization but is not affected by dietary fat. 308 63

We investigated the cytotoxic effects of nitrosoureas with and without a 42-hr preincubation with the ornithine decarboxylase (EC 4.1.1.17) inhibitor alpha-difluoromethylornithine (DFMO, 1 mM) in a MER+ (methylation excision repair positive) human cell line. DFMO combined with a chloroethyl nitrosourea [1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) or 1-(2-chloroethyl)-1-nitrosourea (CNU)] yielded increased toxicity with D37 ratios of 1.9 and 3.3 respectively. There was no enhanced toxicity with the monofunctional nitrosourea 1-ethyl-1-nitrosourea (ENU). BCNU or CNU did not induce DNA-DNA interstrand crosslinks in cells with or without a DFMO pretreatment. DNA single-strand breakage was not increased by addition of DFMO. BCNU-induced DNA-protein crosslinking was decreased in cells pretreated with DFMO. These findings are similar to those in MER- cells in that the chloroethyl carbonium alkylating species is required for the enhanced cytotoxicity seen with DFMO. The ability to form DNA interstrand crosslinks, however, does not appear to be necessary for this toxicity enhancement.
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PMID:alpha-Difluoromethylornithine effects on nitrosourea-induced cytotoxicity and crosslinking in a methylation excision repair positive (MER+) human cell line. 311 77

The present study determined if the decline in placental progesterone (P4) production that results from administration of the antiestrogen ethamoxytriphetol (MER-25) to pregnant baboons results from a change in placental low density lipoprotein (LDL) uptake and/or degradation. Pregnant baboons (Papio anubis) were untreated (n = 10) or received MER-25 (25 mg/kg BW, orally; n = 10) daily on days 140-170 of gestation (term, 184 days). Placentas were removed by cesarean section on day 170 of gestation, and villous tissue was dispersed with 0.1% collagenase at 37 C for 40 min. Placental cells (10(6)) were incubated in medium 199 (pH 7.2) for 12 h at 37 C with increasing amounts (5-100 micrograms) of [125I]LDL, with or without a 100-fold excess of unlabeled baboon LDL. Mean (+/- SE) peripheral serum P4 concentrations on days 140-170 of gestation were 51% lower (P less than 0.01) in MER-25-treated (5.7 +/- 0.3 ng/ml) than in untreated (11.6 +/- 0.5 ng/ml) baboons. The uptake of LDL was 56% lower (P less than 0.01) in placental cells from antiestrogen-treated (6.3 +/- 1.6 ng/micrograms cell protein) than in those from untreated (14.4 +/- 1.9 ng/micrograms cell protein) baboons. The dissociation constants for placental LDL uptake, as assessed by Scatchard analysis, however, were similar in untreated (0.80 microgram/ml) and MER-25-treated (0.76 microgram/ml) animals. The amount of [125I]LDL concomitantly degraded by cells from baboons that received MER-25 was 54% of that degraded by cells from untreated controls. The relative decline in LDL degradation by cells of antiestrogen-treated baboons was proportionate to the decline in overall LDL uptake. The results indicate, therefore, that antiestrogen treatment decreased the amount of placental LDL uptake, but did not change the affinity for the lipoprotein. We suggest that the decline in placental P4 production elicited in pregnant baboons by antiestrogen results, at least in part, from subnormal LDL uptake. We propose that one of the mechanisms by which estrogen regulates the biosynthesis of P4 by the placenta during baboon pregnancy is by increasing receptor-mediated placental cell uptake of cholesterol in the form of LDL. Estrogen, therefore, may regulate LDL uptake by the placenta and thus the availability of cholesterol for P4 biosynthesis via the LDL pathway.
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PMID:Effect of the antiestrogen ethamoxytriphetol (MER-25) on placental low density lipoprotein uptake and degradation in baboons. 335 75


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