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 potent carcinogen N-nitrosodiethanolamine (NDELA) which is nonmutagenic in standard modifications of the S. typhimurium/mammalian microsome assay, can be activated effectively by alcohol dehydrogenase/NAD (ADH/NAD) to intermediates which are directly mutagenic in strains TA 98 and TA 100. The expected metabolites N-nitroso-2-hydroxymorpholine (NHMor), N-nitroso-(2-hydroxyethyl)-glycine (NHEG), N-nitrosoiminodiacetic acid (NIDA), and glycolaldehyde were assayed for their direct mutagenic activities in S. typhimurium TA 1535, TA 98, and TA 100. All compounds were clearly mutagenic in TA 100, but different specificities were observed for the other strains. NDELA and its putative mutagenic metabolites were also tested for induction of genotoxic activities by determination of DNA single strand breaks in primary rat hepatocytes. In these cells, NDELA and NHMor were clearly genotoxic, whereas NHEG and NIDA were inactive. In contrast, when assayed for the induction of selective DNA amplification NDELA and its metabolites were not found to induce SV40 DNA synthesis in SV40-transformed Chinese Hamster cells. The compounds were also assayed for induction of DNA single strand breaks in the liver after a single oral application to rats. NDELA and NHMor were about equally active in this in vivo test, whereas NHEG, NIDA and glycolaldehyde were inactive. Differences in biological activity in the cultivated cells, as compared to hepatocytes or to the in vivo situation may most probably be due to differences in metabolism and/or pharmacokinetics.
J Cancer Res Clin Oncol 1986
PMID:Biological activity of N-nitrosodiethanolamine and of potential metabolites which may arise after activation by alcohol dehydrogenase in Salmonella typhimurium, in mammalian cells, and in vivo. 300 88

In some instances, tumors can produce signs and symptoms at a distance from the tumor or its metastases. These are defined as paraneoplastic syndrome or humoral syndrome associated with neoplasms. Paraneoplastic syndromes can arise from circulating substances secreted by tumors. The most well-recognized and frequent concomitant of neoplasms is the production of hormones by nonendocrine tumors. These are usually called ectopic hormone-producing tumors and bring about clinically endocrinologic manifestations secondary to hormone excess in patients with nonendocrine tumors. Paraneoplastic endocrine syndromes frequently observed are Cushing's syndrome due to ectopic production of ACTH, SIADH due to ectopic production of ADH, hyper-calcemia, hypoglycemia and so on. In order to establish a paraneoplastic etiology for alteration in hormone production, evidence that the hormone is produced by the tumor must be proved. Paraneoplastic endocrine syndromes should be distinguished from hormone production by benign cells, hormone production by a malignancy of an endocrine organ or alterations in hormone production being due to infiltration into the endocrine organ by a primary tumor. The treatment of ectopic endocrine syndromes should be directed primarily at the tumor. Because the course of this type of syndrome usually runs parallel to the course of the underlying tumor, the ectopically produced hormone can be a useful monitoring marker of the disease.
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PMID:[Paraneoplastic endocrine syndromes]. 301 95

Pyrazole (NSC-45410) is a low molecular weight, heterocyclic compound which has been considered for reevaluation in the clinic as a potential cytotoxic agent (Fig. 1). Discovered in 1893, pyrazole is best known as an inhibitor of liver alcohol dehydrogenase (ki = 0.2 uM), and as a result, has been used extensively in studies of alcohol metabolism. In 1960, pyrazole was identified as being active in preclinical antitumor models, which led to preliminary clinical testing. The early Phase I studies were not followed by disease specific Phase II trials, and the clinical activity of the drug has never been evaluated. This omission was noted by the National Cancer Institute's Project for the Review of Old Drugs (PROD), at which time it was also noted that pyrazole is selectively toxic to thyroid tissue in an animal model. Hence, interest in pyrazole was revived for two reasons: (a) failure to screen it for clinical activity in the 1960's, and (b) current interest in discovering drugs with selective toxicity to specific tissues for evaluation of their activity in malignancies arising in the target tissue. In this review, we summarize the evidence which has accumulated concerning pyrazole's potential role as an anticancer agent.
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PMID:Pyrazole: preclinical reassessment. 306 85

Using male Fischer 344 rats classified as young (2-4 months), middle aged (12-14 months), and old (22-25 months), the activities of several Phase I and Phase II biotransformation pathways in the large intestine were investigated, including benzo[a]pyrene hydroxylase (BPOH), alcohol dehydrogenase (ADH), glutathione S-transferase (GST), glutathione peroxidase (GSH-PX), beta-glucuronidase (BG), and microsomal and nuclear glucuronyltransferase (UDPGT). Levels of oxidized (GSSG) and reduced (GSH) glutathione and uridine 5'-diphosphoglucuronic acid (UDPGA) were also measured. BPOH increased 33% in old rats, while ADH and BG activity remained unchanged with age. Nuclear UDPGT remained unchanged with age, whereas form I of GSH-PX declined slightly in old rats. GST, microsomal UDPGT, and form II of GSH-PX declined by 38, 37 and 44%, respectively, in old rats. The decrease in GST and microsomal UDPGT was also significant in middle aged rats. Levels of colonic GSH, GSSG and UDPGA were found to be unchanged with age. These in vitro data suggest the possibility that if reactive intermediates are generated to the same extent in old rats as in young rats, decreased detoxification mechanisms in the old rat may increase susceptibility of the colon to actions of chemical carcinogens.
Cancer Lett 1987 Sep
PMID:Changes in phase I and phase II biotransformation with age in male Fischer 344 rat colon: relationship to colon carcinogenesis. 311 59

On the administration of 3'-methyl-N,N-dimethyl-4-aminoazobenzene to rats pure aminoazo dye-bound alcohol dehydrogenase accounting for 45% of the total soluble protein bound aminoazo dye is isolated from the liver soluble supernatant. Tryptic digestion of that purified aminoazo dye-bound enzyme yields an aminoazo dye-bound nonapeptide which has a sequence identical to amino acids 301-309 in the known sequence of alcohol dehydrogenase (H. Jornvall and O. Markovic, Eur. J. Biochem., 29 (1972) 167-174) with the exception of methionine 306 which is replaced by an aminoazo dye modified amino acid. The nature of the aminoazo dye adduct was determined by studying the structure of the related tetrapeptide obtained by Pronase B digestion and shown by proton NMR spectroscopy and fast atom bombardment mass spectroscopy to have the structure 3-(Val. Asn. Pro. Homocystein-S-yl)-4-methylamino-3'-methylazobenzene. This carcinogen-protein adduct is assumed to arise from attack of the ultimate carcinogenic metabolite, N-sulphonyloxy-4-methylamino-3'-methylazobenzene (FF. Kadlubar, J.A. Miller and E.C. Miller, Cancer Res., 36 (1976) 2350-2359) at the sulphur of methionine 306 followed by spontaneous S-demethylation. This highly specific reaction of carcinogen with alcohol dehydrogenase lowers its Vmax and increases its Km with cyclohexanone thereby reducing its catalytic efficiency for this substrate. This highly specific reaction of the carcinogen with alcohol dehydrogenase may be regarded as a major detoxication reaction.
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PMID:The binding of an aminoazo dye carcinogen to a specific methionine residue in rat liver alcohol dehydrogenase in vivo. 312 Nov 96

Different pathways of alcohol metabolism, the alcohol dehydrogenase pathway, the microsomal ethanol-oxidizing system and the catalase pathway are discussed. Alcohol consumption leads to accelerated ethanol metabolism by different mechanisms including an increased microsomal function. Microsomal induction leads to interactions of ethanol with drugs, hepatotoxic agents, steroids, vitamins and to an increased activation of mutagens/carcinogens. A number of ethanol-related complications may be explained by the production of its first metabolite, acetaldehyde, such as alterations of mitochondria, increased lipid peroxidation and microtubular alterations with its adverse effects on various cellular activities, including disturbances of cell division. Nutritional factors in alcoholics such as malnutrition are discussed especially with respect to its possible relation to cancer.
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PMID:International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC Working Paper No. 15/2. Metabolism and metabolic effects of ethanol, including interaction with drugs, carcinogens and nutrition. 331 28

Treatment of male mice with 20 mg/kg dimethylhydrazine (DMH) s.c. for 10 weeks caused a mean tumour rate of 3.5 after 20 weeks. Dietary iron (3.5% Fefumarate for 10 weeks) enhanced the mean tumour rate to 13.9. All tumours detected were localized exclusively in the distal colon and rectum. The iron load caused a 6.5-fold increase in the mucosal Fe-concentration in the proximal as well as distal colon. DMH-demethylase activity was not influenced by iron and did not differ between proximal and distal segments. Cytosolic alcohol dehydrogenase (ADH) activity was also not altered by iron, but was 3.3-fold higher in the distal colon and rectum as compared to proximal segments; this might explain the DMH-induced tumorigenesis in the distal colon only. It is suggested that iron ions might evoke cocarcinogenic activity by a stimulation of cell proliferation.
Cancer Lett 1988 Aug 30
PMID:Dietary iron enhances the tumor rate in dimethylhydrazine-induced colon carcinogenesis in mice. 340 3

Inhibition of sulfotransferase by 2,6-dichloro-4-nitrophenol (DCNP) has been found to completely abolish the genotoxic potential of N-nitrosodiethanolamine (NDELA) in rat liver as indicated by induction of DNA single strand breaks. The DNA strand breaking potential of N-nitroso-2-hydroxymorpholine (NHMOR), a metabolite of NDELA formed by alcohol dehydrogenase-mediated oxidation, was also almost quantitatively abolished. In contrast to these beta-hydroxylated nitrosamines, the effectiveness of N-nitrosodiethylamine (NDEA) remained unaffected by DCNP with respect to its DNA damaging potential. N-Nitrosoethylethanolamine (NEELA) was the most potent genotoxic agent of this series of nitrosamines and its strand breaking activity was only partially inhibited by DCNP. A new activation mechanism for NDELA is proposed: NDELA is transformed at first by alcohol dehydrogenase into the cyclic hemiacetal NHMOR. This cyclic beta-hydroxynitrosamine appears to be a substrate for sulfotransferase. The resulting sulfate conjugate is suggested to be the ultimate genotoxic electrophile. However, the results do not exclude the possiblity that NDELA itself undergoes sulfate conjugation.
J Cancer Res Clin Oncol 1986
PMID:N-nitrosodiethanolamine is activated in the rat to an ultimate genotoxic metabolite by sulfotransferase. 345 49

The effect of the mixed-function oxidase inhibitor phenylimidazole (PI) and the amine oxidase inhibitors iproniazid (IPRO) and aminoacetonitrile (AAN) on the mutagenic activity of various carcinogens was determined in intrasanguineous host-mediated assays, using mice as hosts and E. coli 343/113 as an indicator of mutagenic activity. The carcinogenic compounds dimethyl-, diethyl-, methylethyl-, and diethanolnitrosamine (DMNA, DENA, MENA, and DELNA respectively) and 1,2-dimethylhydrazine (SDMH) were administered i.p. to mice pretreated or not with one of the inhibitors. After 4 h exposure to each of the carcinogens, E. coli cells recovered from the liver of non-pretreated mice showed considerable induction of VALr mutations; after pretreatment of the hosts with the three inhibitors, significant reduction of the amounts of induced mutants in vivo was observed. Particularly, PI proved a very efficient inhibitor of DENA, MENA, DELNA, and SDMH mutagenicity (93%-97% reduction), suggesting that these carcinogens are mainly activated by cytochrome P-450-dependent enzymes. However, since PI might also inhibit the NAD-mediated activation of DELNA by alcohol dehydrogenase (ADH), the present experiments do not rule out an additional role of ADH in the in vivo mutagenic activation of DELNA. AAN and IPRO were less and much less effective, respectively, in reducing the mutagenic activity of all compounds. Surprisingly, PI showed less inhibition of the mutagenic activity of DMNA (60% reduction), as compared to the other carcinogens; this indicates that metabolic routes other than the cytochrome P-450-dependent enzyme system may be important for the activation of DMNA.
J Cancer Res Clin Oncol 1986
PMID:The effect of mixed-function oxidase and amine oxidase inhibitors on the activation of dialkylnitrosamines and 1,2-dimethylhydrazine to bacterial mutagens in mice. 352 73

Mechanisms of DNA adduct formation by antineoplastic 2-chloroethyl-N-nitrosoureas (CNUs) and of DNA damage induced by these compounds as well as by carcinogenic 2-hydroxyalkylnitrosamines are discussed. CNUs are monofunctional and bifunctional alkylating agents that form, in a quantitatively minor reaction, DNA-DNA crosslinks (XL). In vitro, by far the most abundant alkylation products of DNA are those resulting from 2-hydroxyethylation. The reaction sequence responsible for 2-hydroxyethylation comprises intermediate oxazolidine ring closure followed by generation of 2-hydroxyethylnitrosourea and ethylene oxide. Oxadiazolium intermediates have not been found to play a role. In contrast to the in vitro experiments, in vivo 2-hydroxyethyl adducts are formed to a much lesser extent und 2-chloroethyl adducts are predominant in rat kidney DNA. 2-Hydroxyethylation of phosphate groups introduces extreme instability into the sugar-phosphate backbone since the resulting phosphotriester rapidly breaks down through a dioxaphospholane ring intermediate. Measurements of DNA XL in target tumor tissue and in bone marrow provides a sensitive tool for evaluation in bone marrow provides a sensitive tool for evaluation of hormone-linked cytotoxic agents. The potent environmental carcinogen N-nitrosodiethanolamine (NDELA) has been found to be activated in the rat liver by a two-step metabolic transformation sequence involving alcohol dehydrogenase and, subsequently, sulfotransferase. Evidence for this mechanism is provided by measuring DNA single strand breaks in rat liver DNA and by studying the effect of various enzyme inhibitors on the extent of DNA damage induced in vivo by NDELA and its metabolites.
J Cancer Res Clin Oncol 1986
PMID:DNA adducts and DNA damage by antineoplastic and carcinogenic N-nitrosocompounds. 353 42


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