Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: DrugBank:EXPT00568 (ascorbate)
 23,072 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incubation of rat-liver microsomes, previously azide-treated to inhibit catalase, with H2O2 caused a loss of cytochrome P-450 but not of cytochrome b5. This loss of P-450 was not prevented by scavengers of hydroxyl radical, chain-breaking antioxidants or metal ion-chelating agents. Application of the thiobarbituric acid (TBA) assay to the reaction mixture suggested that H2O2 induces lipid peroxidation, but this was found to be due largely or completely to an effect of H2O2 on the TBA assay. By contrast, addition of ascorbic acid and Fe(III) to the microsomes led to lipid peroxidation and P-450 degradation: both processes were inhibited by chelating agents and chain-breaking antioxidants, but not by hydroxyl radical scavengers. H2O2 inhibited ascorbate/Fe(III)-induced microsomal lipid peroxidation, but part of this effect was dues to an action of H2O2 in the TBA test itself. H2O2 also decreased the colour measured after carrying out the TBA test upon authentic malondialdehyde, tetraethoxypropane, a DNA-Cu2+/o-phenanthroline system in the presence of a reducing agent, ox-brain phospholipid liposomes in the presence of Fe(III) and ascorbate, or a bleomycin-ion iron/DNA/ascorbate system. Caution must be used in interpreting the results of TBA tests upon systems containing H2O2.
 ...
PMID:The action of hydrogen peroxide on the formation of thiobarbituric acid-reactive material from microsomes, liposomes or from DNA damaged by bleomycin or phenanthroline. Artefacts in the thiobarbituric acid test. 170 34

Using the experimental model of partial hepatectomy in the rat, we have examined the relationship between cell division and lipid peroxidation activity. In rats entrained to a regime of 12 h light/12 h dark and with a fixed 8 h feeding period in the dark phase, partial hepatectomy is followed by a rapid regeneration of liver mass with cycles of synchronized cell division at 24 h intervals. The latter phenomenon is indicated in this study by pulses of thymidine kinase activity having maxima at 24 h, 48 h and 72 h after partial hepatectomy. Microsomes prepared from regenerating livers show changes in lipid peroxidation activity (induced by NADPH/ADP/iron or by ascorbate/iron), which is significantly decreased relative to that in microsomes from sham-operated controls, again at 24 h, 48 h and 72 h after the operation. This phenomenon has been investigated with regard to possible underlying changes in the content of microsomal fatty acids, the microsomal enzymes NADPH:cytochrome c reductase and cytochrome P-450, and the physiological microsomal antioxidant alpha-tocopherol. The cycles of decreased lipid peroxidation activity are apparently due, at least in part, to changes in microsomal alpha-tocopherol content that are closely associated in time with thymidine kinase activity.
 ...
PMID:Studies on the hyperplasia ('regeneration') of the rat liver following partial hepatectomy. Changes in lipid peroxidation and general biochemical aspects. 210 18

The lipophilic o-naphthoquinones beta-lapachone, 3,4-dihydro-2-methyl-2-ethyl-2H-naphtho[1,2b]pyran-5,6-dione (CG 8-935), 3,4-dihydro-2-methyl-2-phenyl-2H-naphtho[1,2b]pyran-5,6-dione (CG 9-442), and 3,4-dihydro-2,2-dimethyl-9-chloro-2H-naphtho[1,2b]pyran-5,6-dione (CG 10-248) (a) inhibited NADPH-dependent, iron-catalyzed microsomal lipid peroxidation; (b) prevented NADPH-dependent cytochrome P-450 destruction; (c) inhibited microsomal aniline 4-hydroxylase, aminopyrine N-demethylase and 7-ethoxycoumarin deethylase; (d) did not inhibit the ascorbate- and tert-butyl hydroperoxide-dependent lipid peroxidation and the cumenyl hydroperoxide-linked aniline 4-hydroxylase reaction; and (e) stimulated NADPH oxidation, superoxide anion radical generation and Fe(III)ADP reduction by NADPH-supplemented microsomes. In the presence of ascorbate, the same o-naphthoquinones stimulated oxygen uptake and semiquinone formation, as detected by ESR measurements. The p-naphthoquinones alpha-lapachone and menadione were relatively less effective than the o-naphthoquinones. These observations support the hypothesis that, in the micromolar concentration range, o-naphthoquinones inhibit microsomal lipid peroxidation and cytochrome P-450-catalyzed reactions, by diverting reducing equivalents from NADPH to dioxygen.
 ...
PMID:Inhibition of microsomal lipid peroxidation and cytochrome P-450-catalyzed reactions by beta-lapachone and related naphthoquinones. 215 43

The enzyme activities, which are influenced by the vitamin C level in tissues, were measured to evaluate the vitamin C activity of erythorbic acid (ErA) in guinea pigs administered ErA. Guinea pigs were divided into two groups: animals in one group (control group) were administered 1, 5, and 100 mg/day ascorbic acid (AsA) and those in the other group (supplemented group) were administered 1, 5, 20, and 100 mg/day ErA for 16 days. At the end of the experimental period, they were sacrificed, blood was collected, and their livers were removed. The activities of liver aniline hydroxylase, of liver acid phosphatase, and of serum alkaline phosphatase, and the content of liver cytochrome P-450 were assayed. The activities of aniline hydroxylase and serum alkaline phosphatase and the content of liver cytochrome P-450 of the guinea pigs administered 1 mg ErA were lower than those of the guinea pigs administered 1 mg AsA. However, the enzyme activities and liver cytochrome P-450 content in the guinea pigs administered 5 mg or more of ErA were similar in level to those in the guinea pigs administered 5 mg AsA. These results suggested that administration of a considerably high amount of ErA to guinea pigs showed a similar vitamin C activity to that of AsA, which might suggest that vitamin C activity of ErA may be more than one-twentieth that of AsA, as has been generally believed.
 ...
PMID:Net vitamin C activity of erythorbic acid in guinea pigs. 229 26

Glyceryl-ether monooxygenase (1-alkyl-sn-glycerol,tetrahydropteridine: oxygen oxidoreductase, EC 1.14.16.5) catalyzes the oxidative cleavage of 1-O-alkyl glycerol or glycol derivatives to a long-chain aldehyde and the glycerol or glycol derivative. The specificity for tetrahydropterins of a similar, perhaps identical, enzyme that cleaves O-hexadecyl ethylene glycol in rat liver microsomes was examined with the use of an assay based on [1-3H]ethylene glycol formation from 2-hexadecyloxy [1-3H]ethan-1-ol. Several tetrahydropterin derivatives are effective electron donors for this reaction, and 2,4,5-triamino-6-hydroxypyrimidine is somewhat effective, but NADH, NADPH, ascorbate, reduced dichlorophenolindophenol and glutathione are inactive. Tetrahydropterin derivatives differ from each other in apparent Km and apparent Vmax. The order of increasing apparent Km values is tetrahydropterin approximately 6-methyltetrahydropterin approximately tetrahydrobiopterin less than 6.7-dimethyltetrahydropterin less than tetrahydrofolate. The order of increasing apparent Vmax values is tetrahydrofolate approximately tetrahydropterin less than 6-methyltetrahydropterin approximately tetrahydrobiopterin approximately 6,7-dimethyltetrahydropterin. Results obtained with the use of a spectrophotometric assay, in which tetrahydropterin oxidation is coupled to NADH oxidation by dihydropteridine reductase (NAD(P)H: 6,7-dihydropteridine oxidoreductase, EC 1.6.99.7), indicated that the ratio of 6,7-dimethyltetrahydropterin or 6-methyltetrahydropterin oxidized to ether lipid degraded is about 1.1 to 1.3. Unlike cytochrome P-450-dependent hydroxylases, this alkyl glycol-ether monooxygenase is not inhibited by carbon monoxide. 1-O-hexadecyl-rac-glycerol (chimyl alcohol) competitively inhibits the oxidation of the glycol ether indicating that the same enzyme probably catalyzes the oxidation of both O-alkyl glycol and 1-O-alkyl glycerol.
 ...
PMID:Dependence of an alkyl glycol-ether monooxygenase activity upon tetrahydropterins. 237 98

The effects of vitamin A dietary intake (2 and 20 IU */g of food) on the mutagenic activity of benzo[a]pyrene (B(a)P) toward Salmonella typhimurium (TA98) were studied either in control rats or in animals treated by the PCB congeners 2,4,5,2',4',5'-hexachlorobiphenyl [2,4,5)2Cl) and 3,4,3',4'-tetrachlorobiphenyl [3,4)2Cl). (3,4)2Cl (a planar compound) strongly increased B(a)P monooxygenase (B(a)PMO) activity and glutathione transferase, (2,4,5)2Cl (a non-planar PCB) was a strong inducer of epoxide hydrolase and a weak inducer of B(a)PMO. Enzyme induction was not modified by changes in vitamin A dietary intake. A higher mutagenic effect was observed in the (3,4)2Cl group than in the (2,4,5)2Cl one. This could be related to the specific form of cytochrome P-450 induced by (3,4)2Cl. In the untreated animals, the activation of B(a)P was higher in the 2-IU group than in the 20-IU one. Conversely, in PCB-treated rats the mutagenic activity of B(a)P was higher in the 20-IU group than in the 2-IU one. PCB induction increased the liver content of vitamin C in both the 2-IU and the 20-IU groups but only increased the glutathione levels in the 2-IU groups. This suggests that glutathione content in cellular fractions may be one of the determining parameters for the mutagenic activity of B(a)P.
 ...
PMID:Effects of prototypic PCBs on benzo[a]pyrene mutagenic activity related to vitamin A intake. 249 75

Studies on the modulation of the carcinogen metabolizing enzymes on treatment with masheri extract (ME) and benzo (a) pyrene (B (a)P), were carried out in male Sprague Dawley rats (12 weeks old) fed a nutritionally adequate standard diet. Injection (ip) of ME and B (a) P at 3/4 LD50 dose given in 3 doses at 24 hr interval increased the phase I activating enzymes, viz. cytochrome P-450, benzo (a) pyrene hydroxylase and benzphetamine demethylase while both ME and B (a) P significantly depleted glutathione content and decreased glutathione-S transferase activity. Furthermore, the same treatment of ME and B (a) P significantly depleted the hepatic vitamin A pool while a concommittant increase in vitamin C content was observed.
 ...
PMID:Effect of masheri, a pyrolysed tobacco product on carcinogen metabolizing enzymes. 263 77

1,2-Dibromo-3-chloropropane (DBCP) induced DNA damage, measured by an automated alkaline elution method, in suspensions of rat liver parenchymal cells at low concentrations (1-10 microM). At much higher concentrations (0.5-2.5 mM), DBCP was metabolized to products that were mutagenic to Salmonella typhimurium TA100 co-incubated with the liver cells. At these higher concentrations a marked depletion of cellular glutathione was seen and at 2.5 mM DBCP was cytotoxic. Perdeuterated DBCP (D5-DBCP) caused less DNA damage in the liver cells than DBCP, most likely because of decrease in cytochrome P-450 dependent metabolism. A more pronounced decrease in mutagenicity occurred with D5-DBCP compared to DBCP, whereas the two compounds were equally cytotoxic. Preincubation of the liver cells with diethylmaleate or buthionine sulfoximine, to lower cellular levels of glutathione, decreased DBCP induced DNA damage. The decrease in DNA damage was proportional to the decrease in cellular glutathione levels. In contrast, diethylmaleate enhanced DBCP-induced bacterial mutagenicity and cellular cytotoxicity. The cytotoxic effect could be partly blocked by addition of ascorbate. From the data presented we suggest that: (i) cytochrome P-450 dependent oxidation as well as glutathione conjugation are involved in DBCP induced DNA damage, (ii) cytochrome P-450 dependent oxidation leads to formation of products mutagenic to bacteria and (iii) the cytotoxicity induced by DBCP in the liver cells in vitro is caused by oxidative damage following glutathione depletion and/or direct membrane damage.
 ...
PMID:Different mechanisms are involved in DNA damage, bacterial mutagenicity and cytotoxicity induced by 1,2-dibromo-3-chloropropane in suspensions of rat liver cells. 264 51

Diethylstilbestrol-4',4"-quinone (DES Q) has previously been postulated to be a reactive intermediate in diethylstilbestrol (DES) metabolism. DES is oxidized to DES Q in vitro, but the occurrence of the quinone metabolite in vivo has not yet been demonstrated due to its instability and chemical reactivity. In this report, the characteristics of in vitro formation of DES Q and the isolation of 3H-labeled DES Q from tissue extracts of hamsters injected with radiolabeled DES is described. In vitro, the time-dependent formation of DES Q as a function of microsomal protein, cofactor or substrate concentrations was demonstrated. The microsome-mediated oxidation of DES to quinone was inhibited by various compounds that also effectively inhibit the peroxidatic activity of cytochrome P-450. In vivo, the formation of DES Q occurred in all tissues investigated, livers and kidneys of male and female adult hamsters, neonates and fetuses, and in uterus and placenta. Concentrations of quinone metabolite in liver and kidney of adult hamsters after injection of 75 mumol/kg DES were 76 and 20 pmol/g tissue respectively. In neonates and fetus, concentrations of DES Q after the same dose of DES were markedly less than those in adults (0.026 and 0.047% of adult levels in neonatal liver and kidney and 0.013 and 0.016% of adult levels in fetal liver and kidney respectively). Since DES Q was also formed by fetal liver homogenate in vitro, fetal oxidizing enzymes appear to be the source of the quinone metabolite in this tissue. DES Q concentrations were also examined after injection of DES into hamsters pretreated with vitamin C or alpha-naphthoflavone, substances known to inhibit DES-induced renal carcinogenesis. Quinone metabolite levels were cut in half in response to vitamin C in correlation with the approximately 50% decrease in DES-induced renal tumors reported previously. alpha-Naphthoflavone pretreatment decreased renal and hepatic DES Q concentrations by 70 and 17% respectively, also in correlation with the known prevention of kidney tumors by this flavone. These data support a role of DES Q in DES-induced carcinogenesis. Since there is no correlation between DES Q concentrations and target site specificity of DES induced tumors, the oxidation of DES to DES Q and the genotoxicity of this metabolite may be a necessary but not sufficient event in tumor development. Hormone-dependent growth of initiated cells may also be necessary for the occurrence of cancers.
 ...
PMID:Metabolic oxidation of diethylstilbestrol to diethylstilbestrol-4',4"-quinone in Syrian hamsters. 273 17

Studies on rats treated for 8 months with ethanol (10% solution in drinking water) and simultaneously exposed to xylene vapour (12,000 mg/m3, 5 hr daily) for the last 9 days revealed that the chemicals exert additive stimulatory effect on hepatic microsomal monooxygenase: the activity of aniline p-hydroxylase increased by 380%, microsomal ethanol oxidizing system by 92%, NADPH-cyt. c reductase by 30% and the level of cytochrome P-450 by 70%. The changes were accompanied by a marked proliferation of smooth endoplasmic reticulum (a subcellular site of cytochrome P-450 monooxygenases in the hepatocytes) and an increased NADPH-Fe2+- and ascorbate-Fe2+-driven lipid peroxidation in microsomal membranes--a potential toxic mechanism. Interaction of ethanol and xylene with cytochrome P-450 monooxygenases may enhance metabolic capacity of the liver and in consequence modify biological/toxic effects of occupational exposure to solvents in the case of alcohol abuse.
 ...
PMID:The effect of combined exposures to ethanol and xylene on rat hepatic microsomal monooxygenase activities. 281 36


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