Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 1-year-old child with severe acetaminophen (APAP) poisoning after ingestion of 10 gm APAP demonstrated central nervous system depression, shock, hypothermia, and metabolic acidosis. There was dramatic improvement during treatment with intravenously administered N-acetylcysteine (NAC) and hemodialysis, and the patient recovered without sequelae. A detailed study of APAP metabolism was carried out during the initial 72 hours after ingestion. APAP-sulfate and APAP-glucuronide accounted for 29% and 33%, respectively, of total drug in urine, whereas cysteine and NAC conjugates accounted for only 12%. The low incidence of severe toxicity in children after overdoses of APAP may be related to greater capacity to metabolize APAP via a nontoxic pathway.
 ...
PMID:Metabolism and pharmacokinetics of acetaminophen in a severely poisoned young child. 673 27

Until recently little was known concerning the chemical details of the mechanism of interaction of flavin-linked mitochondrial membrane bound monoamine oxidase (MAO) with its substrates and inhibitors. Substrates which have enzymes as their targets have been valuable in elucidating active site residues and structural features. Acetylenic amines as exemplified by clorgyline, deprenyl and pargyline are called 'suicide inhibitors' because an irreversible inhibitor is formed by the action of MAO from a relatively innocuous compound which acts as a substrate. These inhibitors can selectively inactivate MAO 'type A' and/or 'type B'. MAO isolated in homogeneous form from liver or kidney contains 1 mole of covalently bound coenzyme, cysteinyl-flavin, per mole enzyme. The flavin is bound to a pentapeptide via the thio-ether of cysteine at the 8 alpha-position of the isoalloxazine. A comparison of the inhibitory effects of clorgyline, deprenyl and pargyline on liver enzyme preparations from bovine or rat have confirmed our expectation that these irreversible inactivators form the same type of adduct with the cysteinyl-flavin active site of MAO 'type A' and 'type B', and that binding is stoichiometric at the N-5 of the covalently bound flavin in a flavocyanine linkage. Substrates protect from inhibition. In contrast to the reported observation of Tipton (39), pig brain mitochondrial MAO purified by two alternative methods contains cysteinyl-flavin in substantial amounts. The turnover number of enzyme from brain per mole of cysterinyl-flavin in apparently homogeneous samples is nearly the same as that of highly purified kidney and liver enzyme. Thus it is apparent that brain MAO also contains cysteinyl-flavin at the active center and therefore it is expected that acetylenic as well as hydrazine inhibitors form the same linkage with the flavin moiety as that formed with enzyme from peripheral tissues. A specific inhibitor for the deamination and potentiation of dopamine formed in the brain of Parkinsonian patients after treatment with L-Dopa has been regarded desirable. Deprenyl, a selective MAO 'type B inhibitor without the 'cheese effect', is the most potent inactivator of human brain MAO, and clinical results show that the drug is very useful in the treatment of Parkinson's disease and depression.
 ...
PMID:Biochemical characterization of the active site of brain monoamine oxidase. 678 74

A series of experiments was conducted with crossbred chicks to determine the effects of L-cysteine, copper, and coccidiosis on roxarsone toxicity. Levels of roxarsone in excess of 50 mg/kg depressed performance and increased kidney arsenic concentration. L-cysteine x HCl x H2O (59%) increased rate and efficiency of gain when added to the basal diet, but depressed performance, increased kidney arsenic concentration, and enhanced mortality when added to diets containing toxic levels of roxarsone (200 mg/kg or higher). Moreover, excess copper (500 mg/kg) partially alleviated the gain/feed depression due to the combination of cysteine and roxarsone. Cysteine, in fact, increased feed efficiency in birds fed excess copper in the absence of roxarsone. Eimeria acervulina infection (duodenal coccidiosis) depressed gain and feed efficiency. The depression in feed efficiency was more severe in the presence of roxarsone (50 or 300 mg/kg). In the absence of coccidiosis, 50 mg/kg roxarsone slightly increased gain/feed ratio.
 ...
PMID:Roxarsone toxicity in the chick as influenced by dietary cysteine and copper and by experimental infection with Eimeria acervulina. 708 2

Three experiments were conducted with 9-d-old crossbred chicks to determine the effect of supplemental L-cysteine.HCl.H2O on tolerance to excess dietary Cd. Cd levels of 30 or 60 mg/kg added to a fully fortified corn-soybean meal diet depressed both body weight gain and gain:feed ratio and increased kidney Cd concentration. Supplemental cysteine (i.e., .59% L-cysteine.HCl.H2O) did not alleviate the depression of weight gain or gain:feed ratio due to Cd feeding but did decrease kidney Cd accumulation. Eimeria acervulina infection (i.e., duodenal coccidiosis) depressed rate and efficiency of weight gain and resulted in increased Cd concentrations in kidney tissue. Cystein supplementation increased kidney cadmium concentration even further in E. acervulina-infected birds.
 ...
PMID:Tolerance of the chick to excess dietary cadmium as influenced by dietary cysteine and by experimental infection with Eimeria acervulina. 709 21

The mechanism of the metabolic pathway of acrylonitrile to cyanide (and subsequently to thiocyanate which is excreted in the urine) was already previously confirmed by our work in vitro as well as in vivo. This metabolic route of AN via glycidonitrile and glycolaldehyde cyanohydrin is not the dominant pathway in the total balance of AN metabolism and does not elucidate the fate of the predominant amount of AN. By means of AN labelled with 14C on the nitrile group it was confirmed that, when different routes of administration are used, AN forms in the rat the main portion of radioactivity excreted in the urine in "non-thiocyanate" metabolites. Based on reflection on the reactivity of AN the assumption was expressed that possible metabolites of AN may be S-(2-cyanoethyl)cysteine (CEC) or N-acetyl-S-(2-cyanoethyl)cysteine (AcCEC), so called AN-mercapturic acid. Both these substances were synthetized in our laboratory and used as standards on paper chromatography of urine of animals exposed to AN. Evidence was provided that the main metabolite of AN in rats and rabbits is AcCEC. In the urine of rats 8 hours following administration of AN-14CN in addition to AcCEC another metabolite appears the structure of which was not elucidated so far. By means of preparative paper chromatography of the methylene chloride extract of rabbit urine obtained after subcutaneous injection of AN it proved possible to isolate AcCEC in the form of its dicyclohexyammonium salt. This salt did not produce a depression of the melting point with the synthetically prepared standard. This proved unequivocally the identity of the two substances.
 ...
PMID:New findings on acrylonitrile metabolism. 722 25

The role of glutathione in the biological effects of cyclophosphamide (CP) was evaluated by investigating the following: effect of CP on hepatic glutathione levels; relationship between hepatic glutathione depletion (repletion) and the binding of [chloroethyl-3H]CP and [4-14C]CP to hepatic macromolecules; effects of interaction between CP (or acrolein) and diethyl maleate (a classical glutathione depletor), and/or between CP and cysteine on the binding of labeled CP to hepatic macromolecules, on the induction of hematuria, on the content of hepatic cytochrome P-450, on weight gain in rats, on survival in mice, and on the chemotherapeutic efficacy of CP against Walker 256 carcinoma in rats. CP and acrolein produced dose-dependent depletion of hepatic glutathione in mice, whereas phosphoramide mustard was at least one order of magnitude less effective. Acrolein caused death in mice; CP became covalently bound to hepatic macromolecules, prevented weight gain in rats, and produced hematuria and depression of hepatic cytochrome P-450 in vivo. These effects of CP (or acrolein) were enhanced by diethyl maleate but partially blocked by cysteine. On the other hand, reduction in the volume of Walker 256 carcinoma in rats by CP was not antagonized by cysteine. All these investigations point to the following conclusions: (a) acrolein produced during the metabolism of CP binds to proteins and, by doing so may denature these proteins; and (b) acrolein in vivo preferentially reacts with glutathione, and sulfhydryl-containing compounds may protect against acrolein toxicity and at the same time not interfere with the chemotherapeutic activity of CP.
 ...
PMID:Role of glutathione in the metabolism-dependent toxicity and chemotherapy of cyclophosphamide. 726 Sep 17

Three experiments were conducted to investigate the interaction of cobalt with sulfur-containing amino acids in the chick. Fortified corn-soybean meal diets were fed and tissue concentrations of cobalt were assessed. In Experiment 1, three levels of cobalt (0, 250, and 500 microgram/g) were fed in the presence and absence of .50% supplemental DL-methionine. Dietary additions of cobalt depressed growth rate and caused cobalt accumulation in the liver and kidney. Supplemental methionine in excess of the requirement for maximal chick weight gains partially alleviated the depression in performance and decreased cobalt accumulation in the liver and kidney. Two levels of cobalt (0 and 500 microgram/g) were fed in the presence and absence of .59% supplemental L-cysteine.HCl.H2O (isosulfurous to .50% DL-methionine) in Experiment 2. Again, cobalt depressed performance and accumulated in the liver and kidney. The surfeit of cysteine increased weight gain and decreased cobalt accumulation in the liver but not in the kidney. In Experiment 3, two levels of cobalt (0 and 250 microgram/g) were fed in the presence and absence of two levels of excess DL-methionine (.50 and 1.0%) or two levels of excess cysteine.HCl.H2O (.59 and 1.18%). Multiple linear regression analysis of gain on sulfur consumed from methionine or cysteine indicated that cysteine was almost 6 times more efficacious than methionine in alleviating cobalt toxicity. In fact, cysteine supplemented at a level of 1.18% completely alleviated the growth depression caused by 250 microgram/g cobalt. Both methionine and cysteine reduced cobalt accumulation in the liver and kidney, but the liver was affected to a greater extent than the kidney.
 ...
PMID:The effect of methionine or cysteine on cobalt toxicity in the chick. 726 58

Several lines of investigation were pursued to understand mechanisms involved in the in vivo depression of rat hepatic microsomal mixed function oxidase by cyclophosphamide, an important anti-cancer and immunosuppressive agent. Essentially exclusive metabolism-dependent binding to microsomal proteins of 14C from [4-14C]cyclophosphamide, compared with 3H from [chloroethyl-3H]cyclophosphamide, suggests the binding of the metabolite acrolein. Of the various metabolites and analogs of cyclophosphamide tested (which did not contain a peroxy or a hydroperoxy group), only acrolein and 4-hydroxycyclophosphamide (which releases acrolein in solution) caused denaturation of microsomal cytochrome P-450 in vitro; this denaturation was identical with that produced by sulfhydryl reagents. Of the various chemicals tested, only those which contained either a free amino group (except lysine) and/or a free sulfhydryl group (e.g. semicarbazide, cysteine, glycine, glucosamine) effectively blocked (40-80%) the binding of 14C as well as protected against acrolein-induced denaturation of cytochrome P-450. These data further suggested interaction of cyclophosphamide metabolite with free amino and/or free sulfhydryl groups in proteins. However, comparison with [3H]aflatoxin B2a which interacts with free protein amino groups via the formation of Schiff bases, clearly attributed the preferential binding of 14C to cysteine sulfhydryl groups in these proteins. Studies on chemical models derived from reaction between acrolein and cysteine also supported this suggestion. When microsomes isolated from incubations metabolizing [4-14C]cyclophosphamide were subjected to gel electrophoresis, the major radioactive band detected by autoradiography was associated with a cytochrome P-450 band at 55,000 daltons, the major band induced by phenobarbital in the rat. All these results taken together strongly point to the possibility that acrolein is the cyclophosphamide metabolite responsible for the depression of the mixed function oxidase activities. Acrolein most likely produces this effect by alkylation of the sulfhydryl group(s) in the active site of cytochrome P-450.
 ...
PMID:Studies on the mechanism of denaturation of cytochrome P-450 by cyclophosphamide and its metabolites. 729 26

Studies were continued with both chicks and rats on the previously reported (featherston and Rogler, 1978) growth depression observed when a crystalline amino acid diet adequate in all nonsulfur-containing amino acids and containing .2% DL-methionine and .2% L-cystine was supplemented with an additional .2% L-cystine. In the present investigation, an average growth depression of 37% was observed in chicks fed a diet containing .4% L-cystine and .2% DL-methionine as compared with chicks fed a diet containing .2% L-cystine and the same level of methionine. A comparable depression was noted when cystine was replaced by L-cysteine. In contrast, an additional .2% of another amino acid (L-tryptophan) did not depress growth. When the high and low cystine diets were meal-fed, results obtained were similar to those observed with ad libitum feeding, but the magnitude of the difference was reduced. Foot-pad lesions, similar to those described in turkey poults fed methionine-deficient diets, were observed in two experiments. Factorial analysis of plasma amino acids indicated that the total of all amino acids analyzed was significantly (P < .05) higher in chicks fed the lower cystine or cysteine diets. Plasma methionine was slightly lower (P < .10) but plasma cystine was significantly (P < .05) higher in chicks fed the cystine or cysteine supplemented diets. A study with .2 and .4% L-cystine and 200, 600, and 2000 mg/kg of choline (factorial design) demonstrated a significant (P < .05) depression in weight gain due to the added L-cystine, no significant (P < .05) differences due to choline, and the absence of a cystine-choline interaction. No detrimental effects were observed when weanling rats were fed a crystalline amino acid diet containing .1% DL-methionine and .2% L-cystine supplemented with additional L-cystine.
 ...
PMID:Methionine-cystine interrelationships in chicks and rats fed diets containing suboptimal levels of methionine. 741 90

Glucosinolates, such as sinigrin, and S-methyl cysteine sulphoxide (SMCO), which are found in forage brassica species have been implicated in the low intakes observed among lambs consuming such diets. To test both the individual and interactive effects of these compounds in sheep, all combinations of the sinigrin breakdown products, allyl cyanide (ACN) and allyl isothiocyanate (AITC; 10 mmol/d), and the SMCO metabolite dimethyl disulphide (DMDS; 25 mmol/d) were orally administered twice daily for 5 weeks to forty sheep offered dried grass pellets ad lib. As well as measuring voluntary food intake (VFI), a number of haematological and clinical function tests were conducted to assess the physiological effects of the compounds. VFI was significantly depressed by both ACN and AITC but not by DMDS. DMDS significantly ameliorated the effects of ACN on VFI (P < 0.001). Concentrations of reduced glutathione in the blood were depressed by ACN and AITC and elevated by DMDS but no significant interactions were evident. Elevated plasma gamma-glutamyl transpeptidase (EC 2.3.2.1) activity on ACN and AITC treatments indicated possible liver damage. DMDS elicited a rise in Heinz bodies to 11% by week 2 but this was not reflected in packed cell volume and blood haemoglobin levels which were unaffected by treatment. The increased Heinz body count caused by DMDS was not further influenced by ACN or AITC. In conclusion, the depressive effects of sinigrin breakdown products on VFI were not compounded by the additional presence of DMDS which, on the contrary, lessened the depression of VFI caused by ACN.
 ...
PMID:Effects of oral administration of brassica secondary metabolites, allyl cyanide, allyl isothiocyanate and dimethyl disulphide, on the voluntary food intake and metabolism of sheep. 790 60


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>