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

Levels of mixed-function oxidase (MFO) enzymes were measured in adriamycin(ADR)-sensitive murine leukemia P-388 and its ADR-resistant subline P-388/ADR. The subcellular fractions of the resistant cells showed decreased contents of MFO components, cytochrome P-450 and cytochrome b5, in comparison with the identically prepared fractions of the parental tumor. Similarly, the levels of 7-ethoxycoumarin O-deethylase and the rate of ascorbate induced lipid peroxidation in vitro showed lower values in resistant tumor cells than those of P-388 tumor cells. The observed differences in the two tumor cell types were found to be considerably enhanced if the tumor cells were exposed in vitro to ADR before fractionation. The magnitude of induction of the MFO enzymes was significantly greater in the ADR exposed P-388 cells. The corresponding inducibility was suppressed in the drug exposed resistant tumor cells.
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PMID:Mixed-function oxidase enzymes in adriamycin-sensitive and resistant sublines of P-388 leukemia. 747 10

The vitamin C activity of erythorbic acid (ErA) in ascorbic acid (AsA)-deficient guinea pigs was evaluated. The guinea pigs depleted AsA for 16 days were divided into two groups: one group (control group) was supplemented with 1, 5, or 100 mg/day AsA and the other group (experimental group) was supplemented with 1, 5, 20, or 100 mg/day ErA for 4 days. The contents of AsA and ErA in the tissues of guinea pigs were determined by using HPLC, and the activities of liver aniline hydroxylase, of serum alkaline phosphatase and the content of liver cytochrome P-450 were measured. The AsA tissue content of AsA-supplemented guinea pigs was much higher than the ErA tissue content of ErA-supplemented ones, and also, the activities of liver aniline hydroxylase, of serum alkaline phosphatase and the content of liver cytochrome P-450 of AsA-supplemented animals were much higher than those of ErA-supplemented animals, even when the supplemented amount of ErA was equal to that of AsA. Based on these results, the vitamin C activity of ErA seems to be much lower than that of AsA in the AsA-deficient guinea pigs. This suggested that the apparent vitamin C activity of ErA was dependent on the AsA tissue levels of guinea pigs.
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PMID:Vitamin C activity of erythorbic acid in ascorbic acid-deficient guinea pigs. 761 23

There is a growing body of evidence implicating free radicals in a wide variety of medical diseases and conditions, especially the diseases of ageing, such as cancer and cardiovascular disease, which appear to be ultimate expressions of long-term, cumulative and sustained cellular damage. Vitamin E is an excellent lipid-soluble, chain-breaking antioxidant in the presence of other co-operative antioxidants such as vitamin C or ubiquinol, but it can act as a pro-oxidant in their absence. Epidemiological findings and animal studies support the belief that vitamin E is protective against cardiovascular disease and possibly cancer. The wide range of symptoms associated with vitamin E deficiency is consistent with a loss of antioxidant protection in those long-lived cells in which there is sufficient opportunity for accumulation of free radical damage. The cellular damage is proposed to arise from the generation of free radicals during normal aerobic metabolism. Some susceptible tissues may have enhanced levels of radicals that are produced, for example, by the action of cytochrome P-450 enzymes in steroidogenic tissues, or by the generation of NO in neural tissues.
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PMID:Vitamin E: molecular and biological function. 797 39

2,2-Dimethylchromenes and chromans containing cytochrome P-450 resistant 2,2,2-trifluoroethoxy aryl substituents were synthesized and their activity as lipid peroxidation inhibitors evaluated and compared with that exhibited by the corresponding non-fluorinated derivatives. Lipid peroxidation was stimulated in rat liver microsomes by addition of Fe-ascorbate or NADPH, and determined with the TBARS (thiobarbituric acid reactive substances) test. In assays using Fe-ascorbate stimulation, only those derivatives with a OH group at C6 (i.e. 6 and 12) elicited good inhibitory activities (IC50 = 6.0 and 5.3 microM, respectively). In respect to the NADPH dependent incubations, inhibitory activity of compound 11 (IC50 = 6.0 microM) was the highest found within the 6,7-dialkoxy derivatives tested. Results on metabolism assays with this compound showed the generation of phenol 12 (i.e. the putative active antioxidant species); on the other hand, no metabolite resulting from dealkylation at C7 was detected, thus confirming the resistance conferred by the CF3CH2O group to the cytochrome P-450 promoted cleavage. Finally, in assays where incubations in the presence of NADPH were prolonged up to three hours, inhibitory activity of the non-fluorinated 6,7-dialkoxychroman 8 remained constant, thus suggesting that a continued release of the species responsible for the inhibitory activity was produced. However, inhibition elicited by the fluorinated analog 11 showed a small decrease during the third hour of incubation. This decrease could be attributed to the slight inhibition of the cytochrome P-450 metabolism exerted by substrates bearing the CF3CH2O substituent, which would decelerate the generation of the active phenol species.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of rat liver microsomal lipid peroxidation elicited by 2,2-dimethylchromenes and chromans containing fluorinated moieties resistant to cytochrome P-450 metabolism. 808 55

The specific amounts of the microsomal cytochromes P-450 (P-454) and b5 and the amounts of microsomal protein in liver and renal cortex of guinea pigs depend on the extent of the vitamin C supply to which the animals are adapted (at least 6 weeks). In the case of low supply--with 5 mg vitamin C in 100 g food--which still permits to survive, the amounts of the cytochromes are decreased in both organs (an accumulative supply--every 3.5 days via stomach tube--causes no evident decreases). The reduced amount of cytochrome P-450 gives rise to a corresponding elongation of the sleeping time after injection of evipane; this agrees with other reports upon restriction of metabolic activities by marginal supply. But the amount of the cytochrome is induced as well in these animals by several injections of evipane, to the same level as in animals supplied with more vitamin C. Our early report on a considerable decrease of the specific amount of cytochrome P-450 in the liver by omission of vitamin C for 14 days proves correct only in this organ and when the guinea pigs were previously abundantly supplied with vitamin C. There is no corresponding decrease after an adaptation to medium and lesser supplies of vitamin C. The decrease of the cytochrome after abundant supply seems to be due to a diminished stimulation of its synthesis in connection with modifications in the hormonal control of the metabolism and, thus, is only indirectly connected with the lack of vitamin C. The effects of omission of vitamin C supply probably depend generally on the previous adaptation, at least in the liver. The considerable decrease of the cytochrome P-450 and the simultaneous reduction of the mitochondrial compartment raise the question of if a maximum supply with vitamin C is favorable resp. the physiological optimum.
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PMID:[Characterization of guinea pigs after adaptation to different high vitamin C supplies. 3. Microsomal cytochromes in the liver and kidney]. 823 79

Effect of unsaturated and saturated fats on cholesterol metabolism was studied in ascorbate sufficient and deficient guineapigs. Experimental animals were made chronic ascorbic acid deficient by allowing oral intake of 0.5 mg ascorbic acid/day/animal. Elevation in serum and liver cholesterol and triglyceride along with depression in cholesterol oxidation and 7 alpha-hydroxylation in liver was observed in unsaturated fat fed guineapigs with ascorbate deficiency. Liver microsomal cytochrome P-450 level was found to be low in ascorbate deficient animals. Polyunsaturated fat intake could not lower the serum cholesterol level in ascorbate deficiency. Today polyunsaturated fat in the diet is encouraged all over the world for its hypocholesterolemic effect. This study indicates that polyunsaturated fat intake with ascorbic acid deficiency may produce hypercholesterolemia.
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PMID:Interrelationship of dietary lipids and ascorbic acid with hepatic enzymes of cholesterol metabolic pathway. 927 32

The effects of ascorbic acid (AA) or vitamin C in atherosclerosis has attracted considerable attention; however results of clinical studies are conflicting. Several studies indicate an increase in plasma triglyceride (TG) and cholesterol (CH) levels in guinea pigs (GP) that have been fed a diet containing a minimal amount of AA. Previous studies carried out in GP fed a diet devoid of AA showed a significant decrease in cytochrome P-450 level compared to GP fed high and adequate amounts; however, the level of cytochrome P-450 in the two groups were not significantly different. The enzymes that synthesize TG and CH are located in endoplasmic reticulum which is also the site for cytochrome P-450 synthesis. It is of interest to determine whether there is an association between TG and CH synthesis and cytochrome P-450 induction. Adult male Hartley GP weighing 350-400 g were fed a diet containing 2.5% (Group I), 0.1% (Group II) and 0% (Group III) AA. The food consumption and weight gain were not significantly different in different groups. After feeding the diet for four weeks, half of the animals in each group were starved. Blood was withdrawn and TG and CH were determined in the serum. TG and CH were markedly elevated in both starved and nonstarved Group III GP; however, these levels were not altered in Group 1 and Group II GP. Plasma AA showed significant differences in all three nonstarved and starved groups. Plasma alpha-lipoprotein was decreased and beta-lipoprotein was increased in Group III GP. Hepatic CH and TG were also significantly elevated in Group III GP, and Groups I and II showed no changes. TG and CH showed a negative correlation with cytochrome P-450, whereas CH and TG showed a positive correlation. We conclude that AA deficiency causes extensive hyperlipidemia, feeding high level of AA does not alter the lipid metabolism and induction ofcytochrome P-450 is inversely related to TG and CH synthesis.
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PMID:Association between hyperlipidemia and hepatic cytochrome P-450 in guinea pigs. 934 27

The antioxidant potential of albumin-bound sulfur (SBA) was investigated in rat liver microsomes using lipid peroxidation systems in vitro. Sulfur bound to protein is a reduced metabolite which is produced from cystine by gamma-cystathionase. Lipid peroxidation was induced either chemically by ferrous ions and ascorbate or enzymatically by carbon tetrachloride or tert-butyl hydroperoxide as indicated by the increase in thiobarbituric acid reactive substances (TBA-RS) and oxygen consumption. Although the antioxidant effect of SBA was weak on the non-enzymatic lipid peroxidation system, the addition of SBA significantly inhibited TBS-RS formation and oxygen consumption compared with non-treated bovine serum alubumin (BSA) in a microsomal lipid peroxidation system induced enzymatically. The sulfur bound to albumin disappeared during incubation with liver microsomes. However, slight differences in the disappearance were observed depending on whether or not lipid peroxidation was induced in the enzymatic systems. In the CCl4-induced lipid peroxidation system, the cytochrome P-450 level was significantly decreased by the addition of SBA. Therefore, in cytochrome P-450 dependent lipid peroxidation system, the potential effects of sulfur bound to albumin are due to an inhibition of cytochrome P-450 rather than by the oxidation itself caused by radical trapping.
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PMID:Antioxidant effects of albumin-bound sulfur in lipid peroxidation of rat liver microsomes. 1037 61

Ethanol was given to male Wistar rats as an acute dose (5 g/kg) or continuously at 5% (w/v) in a liquid diet to provide 36% of the caloric requirement. Free radicals generated in the liver were collected as a stable adduct in bile following the in vivo administration of the spin trapping agent alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN; 700 mg/kg). [1-(13)C]ethanol was used to confirm the formation of the 1-hydroxyethyl radical and to demonstrate that this was ethanol-derived in the case of the single-dose treatment. Free radical production increased up to 1h after the acute dose and then plateaued over the next 30 min. During chronic exposure to ethanol, free radical generation increased significantly after 1 week and then declined again to remain at a low level over the next 2 weeks; this transient increase corresponded closely with the induction of cytochrome P-450 2E1 (CYP 2E1) in response to ethanol feeding. Single-cell electrophoresis was used to investigate effects on DNA. After an acute dose of ethanol, the frequency of single-strand breaks increased from 1 h to peak at 6 h but then declined again to control values by 12 h. During the chronic exposure, an increase in the frequency of DNA breaks was seen at 3 days, reached a peak at 1 week and then decreased slowly over the next 5 weeks. The effects of antioxidants on these parameters was investigated after an acute dose of ethanol. Pre-treatment with vitamin C (400 mg/kg, i.p., daily for 5 days) or vitamin E (100 mg/kg, i.p., for 5 days) prior to the administration of ethanol (5 g/kg) inhibited generation of the 1-hydroxyethyl-POBN adduct by 30 and 50%, respectively, and both agents prevented the increased frequency of DNA single-strand breaks caused by ethanol. The significance of the temporal coincidence of changes in the above parameters in response to ethanol is discussed.
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PMID:Ethanol-induced free radicals and hepatic DNA strand breaks are prevented in vivo by antioxidants: effects of acute and chronic ethanol exposure. 1060 39

The aim of the present work was to determine the pharmacodynamics of antioxidant effect of alpha-tocopherol and its derivatives (alpha-tocopheryl esters and chromanols with different chain-length) in the animal tissues, as well as the role of cytochrome P-450 in biotransformation of these compounds. Alpha-tocopherol and its derivatives were injected intraperitoneally in rats or mice in a single dose of 100 mmol per kg b.w. The animals were sacrificed at different time intervals (0, 1, 2, 4, 8, 12, 24, 36 hours) and the liver, heart, brain and skeletal muscles were removed, homogenized and incubated with lipid peroxidation (LPO) inducers (Fe2+ + ascorbate). LPO was evidenced by the generated malone dialdehyde (MDA). Data were expressed as percentage of LPO inhibition by alpha-tocopherol or its derivatives as compared to control group. The kinetic curves of the inhibitory action of alpha-tocopherol and its derivatives on LPO were characterized by three phases: a phase of increasing antioxidant activity, a phase of maximal antioxidant activity (about 60-95% LPO inhibition), and a phase of decreasing antioxidant activity. Alpha-tocopheryl esters possessed dynamics of antioxidant action the same as alpha-tocopherol. Therefore the hydrolysis of alpha-tocopheryl esters in animal organism is not a limiting factor for their antioxidant effect. The alpha-tocopherol derivatives with short chain-length (C1, C6) had a shorter half-life in animal tissues as compared to alpha-tocopherol or its esters. In vitro experiments showed that C1 and C6 are substrates of cytochrome P-450. In contrast, alpha-tocopherol and its esters did not bind to cytochrome P-450 even at concentrations as high as 10 mmol/l. Apparently, C1 and C6 underwent biotransformation and were excreeted more quickly from the organism.
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PMID:Pharmacodynamic of the antioxidant action of alpha-tocopherol and its derivatives in liver, brain, heart and skeletal muscles. 1114 Jan 88


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