Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.1.1.1 (alcohol dehydrogenase)
 9,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mutagenic activity of diethanolnitrosamine (NDELA), a carcinogenic compound which leads to inconsistent results in standard in vitro procedures was tested in vitro and in animal-mediated assays with the indicator strain Escherichia coli (E. coli) K-12 343/113. This strain allows the simultaneous detection of forward and back mutations arising in several genes of the E. coli chromosome. In animal-mediated assays in which mice were used as hosts for i.v. injected E. coli indicator cells, s.c. application of NDELA induced a dose dependent increase of galactose fermenting mutants in cells recovered from the livers of animals exposed for 3 h to the mutagen. Comparison with results obtained with diethylnitrosamine (DENA) in the same test system revealed that the two compounds apparently cause different types of mutagenic lesions. Induction of arg+ mutations by DENA and several other aliphatic nitrosamines is mainly due to base pair substitutions, whereas NDELA is rather mutagenic in the galRs system. This latter system is, in addition, sensitive to frameshifts and deletions. These differences in mutagenic specificity suggest that NDELA and DENA, although structurally closely related, are activated via different molecular mechanisms. In fact, evidence is accumulating that alcohol dehydrogenase (ADH) could be involved in the activation of NDELA. On the other hand, the effective mutagenesis of NDELA obtained in vitro with E. coli upon addition of rat liver microsomal fraction would not be expected if ADH is involved in the activation since the S-9 Mix used in the present experiments was devoid of cofactors (NAD, NADP), necessary to accomplish oxidation by ADH. Therefore, further in vivo studies were performed, in which pyrazole, a potent blocker of ADH, was administered prior (1 and 24 h) to the injection of the mutagen. The observation that a dose dependent increase of mutants in the liver (and to a lower extent in the spleens) of treated animals takes place under conditions in which ADH activity is blocked, whereas several microsomal enzymes are stimulated, indicated that besides oxidation of NDELA by ADH other metabolic activation pathways are involved. Apparently enzymes contained in the liver homogenate, possibly NADPH dependent enzymes of the microsomal ethanol oxidizing system, play an important role in the formation of mutagenic metabolites of NDELA.
J Cancer Res Clin Oncol 1986
PMID:Studies on the metabolic activation of diethanolnitrosamine in animal-mediated and in vitro assays using Escherichia coli K-12 343/113 as an indicator. 353 44

A water loading test was performed in 10 patients with a cancer of the digestive tract without hyponatremia and in 10 controls. A lowering of the CfH2O was observed in the patients during the test, as well as an increase in the cortisol plasmatic rates, while aldosterone rates remained normal. To valid the hypothesis of a hypervasopressinic state in these patients, 15 cancerous patients and 12 controls had a plasmatic ADH dosage, which pointed indicated higher hormonal level in the first group.
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PMID:[New data on the adrenal-post-pituitary system of cancer patients]. 377 62

Three thousand three hundred three women were followed an average of 17 years following benign breast biopsy. These women comprise 84.4% of those originally targeted for follow-up. Risk of invasive breast cancer development was analyzed in relation to the hyperplasia classification scheme of Wellings et al (JNCI 1975; 55:231-73) that is based on terminal ductal-lobular units (ALA). Cancer risk was also assessed with respect to family history of breast cancer in first-degree relatives (FHBC), as well as atypical features of hyperplasia recognized by resemblance to carcinoma in situ of ductal type (ADH). There was a trend of increasing cancer risk with increasing degree of ALA lesion, reaching 1.9 with ALA-IV lesions having both qualitative and quantitative features of advanced atypical hyperplasia. When ADH lesions are removed from the analysis, any predictive power of ALA lesions is lost. ADH recognizes histologic lesions with a four- to fivefold increased risk of breast cancer. FHBC interacts with any hyperplastic lesion so as to approximately double the cancer risk.
Cancer Detect Prev 1986
PMID:Breast cancer risk of lobular-based hyperplasia after biopsy: "ductal" pattern lesions. 377 6

To elucidate the ectopic hormonal pattern in patients with small cell carcinoma of the lung, plasma ACTH, serum calcitonin, serum gastrin, plasma glucagon, serum insulin, plasma secretin, plasma VIP, serum growth hormone, serum hCG/LH, the total of serum hCG and hCG-beta-subunit,serum alpha-subunit, serum human placental lactogen, urine ADH, urine 5-HIAA, urine VMA, urine HVA, and urine hCG-LH were measured prior to therapy in 75 patients. Twenty-two patients (29%) had elevated plasma ACTH, and 18 of these had concomitant increased values of corticosteroid in a 24-hour urine sample. Forty-eight patients (64%) were found to have elevated serum calcitonin, and one-third of the patients were diagnosed as having the ectopic ADH syndrome. Serum gastrin concentrations were increased in 20% of the patients, but the elevations were marginal in almost all cases. None of the remaining substances was found to be significantly elevated. Concentrations of plasma ACTH, serum calcitonin, and urine ADH were not found to be correlated with the stage of the disease, and no correlation of these substances with the histological subtypes of small cell carcinoma was disclosed.
Cancer 1980 Mar 15
PMID:Hormonal polypeptides and amine metabolites in small cell carcinoma of the lung, with special reference to stage and subtypes. 624 82

The ectopically produced polypeptide hormones ACTH, ADH, and calcitonin were investigated as tumor markers in patients with small-cell carcinoma of the lung (SCC). Plasma ADH concentrations were evaluated separately as well as in relation to concomitantly obtained plasma osmolality levels. No significant nor consistent changes of marker concentrations caused by lysis of tumor cells were found immediately after administration of cytotoxic drugs. After tumor regression, plasma ACTH and serum calcitonin concentrations and inappropriate ADH secretion (plasma ADH levels inappropriately high compared with plasma osmolality) became normal in most cases; however, progressive disease was not followed consistently by changes in plasma ACTH concentrations and occurrence of inappropriate ADH secretion. Contrary to this, among 12 patients with disease progression, serum calcitonin levels increased in ten patients and plasma ADH levels increased in 11 patients. In most cases, however, these changes were only moderate, and serum calcitonin concentrations were found to be increased after tumor regression in patients who had normal pretreatment levels. It is concluded that decisions on treatment of patients with SCC cannot exclusively be based on changes in the concentrations of the polypeptide hormones that might be of ectopic origin.
Cancer 1980 Nov 01
PMID:ACTH, ADH, and calcitonin concentrations as markers of response and relapse in small-cell carcinoma of the lung. 625 49

1. The cancer chemotherapeutic antibiotic, daunorubicin, is metabolized in rabbit liver by two distinct cytoplasmic reductases, with pH optima at 6.0 and 8.5. 2. A comparison of inhibition and activation of these two enzymes provides evidence of biochemical and kinetic differences, and suggests that the enzymes belong to different classes of carbonyl reductases; the pH 8.5 optimum reductase activity is classified as an aldehyde reductase, whereas the pH 6.0 optimum reductase is a ketone reductase.
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PMID:Daunorubicin reduction mediated by aldehyde and ketone reductases. 626 15

The concept that alcohol dehydrogenase (ADH) is involved in the metabolism of methylazoxymethanol (MAM) was examined in a model consisting of two strains of the deer mouse, Peromyscus maniculatus, one of which has a normal complement of the enzyme [ADH(+)], and the other, which completely lacks it [ADH(-)]. Both the ADH(+) and the ADH(-) strains rapidly metabolized [14C]MAM, administered in the form of the acetic acid ester, [14C] MAMOAc , to 14CO2, and the rates and extents of metabolism were virtually identical. Determination of O6-methylguanine and 7-methylguanine in liver DNA 6 and 24 hr after MAMOAc (25 mg/kg) administration showed that the levels of DNA methylation induced by the carcinogen were not significantly different in the two strains, indicating that both are capable of the metabolic activation of MAM to methylating species. Pyrazole, a potent inhibitor of ADH, inhibited MAM metabolism as well as liver DNA methylation in the ADH(+) strain; however similar inhibition of these processes also occurred in the ADH(-) strain. 3-Methylpyrazole, a weak or noninhibitor of ADH, also decreased the levels of MAM metabolism in both the ADH(+) and the ADH(-) strains. From these results, we conclude that ADH is not obligatory either in the metabolism or in the metabolic activation of MAM. As a possible alternative to ADH, liver microsomes were examined for their ability to metabolize MAM. In the presence of a NADPH-generating system, liver microsomes from both strains converted [14C]MAM to 14CH3OH and 14CH2O , although liver microsomes from the ADH(-) strain were more active in this respect. The microsomal metabolism was sensitive to inhibition by CO as well as to inhibition by pyrazole and 3-methylpyrazole.
Cancer Res 1984 Jul
PMID:Non-alcohol dehydrogenase-mediated metabolism of methylazoxymethanol in the deer mouse, Peromyscus maniculatus. 637 98

N-Nitrosodiethanolamine (NDELA), a potent carcinogen, has not so far been found to be mutagenic in a wide range of test systems. In particular, mutagenicity testing in Salmonella typhimurium with rat liver S-9 mix or microsomal fraction used for activation has failed to indicate mutagenicity. However, when incubated with alcohol dehydrogenase (ADH) in the presence of NAD, NDELA is converted to a potent mutagen. A possible mechanism of activation comprises the generation of an aldehyde as a primary metabolite formed by NAD/ADH and its subsequent rearrangement into cyclic intermediates. The latter might either be further metabolized or spontaneously decompose into various alkylating agents and glycolaldehyde. Standard test conditions used for the Ames test will not favor the detection of mutagens to be activated by NAD/ADH because they require the presence of NADPH, whereas ADH needs NAD to become an activating enzyme, as shown for NDELA.
J Cancer Res Clin Oncol 1984
PMID:Alcoholdehydrogenase as an activating enzyme for N-nitrosodiethanolamine (NDELA): in vitro activation of NDELA to a potent mutagen in Salmonella typhimurium. 637 17

The metabolism of [1,2-14C]vinyl bromide (VBR) to products irreversibly bound to DNA and protein was examined in rat liver microsomes, reconstituted cytochrome P-450 systems, and isolated hepatocytes. A role for cytochrome P-450 was confirmed using inhibition and reconstitution experiments. The major form of cytochrome P-450 involved in VBR metabolism does not appear to be either of the major isozymes induced by phenobarbital or beta-naphthoflavone, as determined by induction, reconstitution, and antibody inhibition studies. 2-Bromoethylene oxide and 2-bromoacetaldehyde, suspected metabolites of VBR, were synthesized and found to be substrates for rat liver epoxide hydrolase and equine liver alcohol dehydrogenase, respectively. These enzymes were used to probe the roles of the two possible metabolites in the irreversible binding of products of VBR to protein and DNA. Alcohol dehydrogenase was more effective than epoxide hydrolase in inhibiting the binding of VBR metabolites to protein in microsomal incubations. Epoxide hydrolase was effective in inhibiting the binding of VBR or vinyl chloride metabolites to calf thymus DNA added to such systems, but alcohol dehydrogenase was not. Similar results were obtained for binding of VBR metabolites to DNA in a reconstituted enzyme system. Reduced glutathione blocked nonenzymatic binding of 2-bromo[1,2-14C]acetaldehyde to protein but not DNA. Binding of vinyl chloride and VBR metabolites to protein was blocked by reduced glutathione, but binding to DNA was not. These results are consistent with the view that 2-haloethylene oxides are the major alkylating agents bound to DNA, and 2-haloacetaldehydes are the major alkylating agents bound to protein in these experimental systems. Studies with labeled 2-bromoacetaldehyde indicate that the slow kinetics of DNA binding by this compound is responsible in part for this phenomenon. Studies with isolated rat hepatocytes suggest that a significant portion of the total and reactive metabolites are able to leave these cells. In these systems, binding of metabolites of vinyl chloride to DNA outside the hepatocytes could be partially blocked by epoxide hydrolase or by alcohol dehydrogenase, implying that, as target farther away from sources of reactive species are considered, the stabilities of these species become more important for reaction with nucleophilic sites.
Cancer Res 1981 Nov
PMID:Roles of 2-haloethylene oxides and 2-haloacetaldehydes derived from vinyl bromide and vinyl chloride in irreversible binding to protein and DNA. 703 Apr 76

The normal level of human serum alcohol dehydrogenase (EC 1.1.1.1) (ADH) activity which is not measurable by conventional methods was found to be within the range 0.07-0.56 U/1 when measured by a sensitive method based on a coenzyme recycling reaction. In different liver diseases the normal upper limit of serum ADH activity was found to be exceeded up to 70 times. Although ADH activity under pathological conditions usually parallels that of other enzymes, e.g., sorbitol dehydrogenase (EC 1.1.1.14) (SDH) and alanine transaminase (EC 2.6.1.2) (ALT), its relative elevation above the upper normal limit is generally greater, particularly in the early stages of viral hepatitis. Observations on some patients also suggested that very early stages of liver damage, caused by drugs or secondary malignancy, could be detected by increases of serum ADH activity when the activities of some other liver specific enzymes were still within their normal values. A pilot experiment on rats, intoxicated with carbon tetrachloride, showed that serum ADH activity could reflect acute liver parenchymal damage more sensitively than SDH and ALT activity.
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PMID:Serum alcohol dehydrogenase activity in liver diseases. 703 78


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