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

In rats, 3 days treatment with paracetamol (1 oral dose of 1 g/kg daily) produced a complete protection against the hepatotoxic actions of a further dose of paracetamol as documented by determination of serum enzyme activities (glutamic-oxaloacetic transaminase, (GOT), glutamic-pyruvic transaminase (GPT), sorbitol dehydrogenase (SDH), bromsulphthalein retention and histological investigations. Subacute paracetamol treatment decreased liver glutathione levels by 46%, liver microsomal cytochrome P-450 content by 23%, hepatic hydroxylation of aniline by 29% and hepatic demethylation of aminopyrine by 46%. It afforded also some protection against the hepatotoxic actions of carbon tetrachloride, bromobenzene and thioacetamide, but did not influence the antiphlogistic activity of paracetamol (carrageenan paw edema test). Plasma and liver concentrations of free paracetamol after oral administration of 1 g/kg paracetamol were somewhat higher in the subacutely paracetamol-pretreated rats than in the non-pretreated control animals whereas no differences in the concentrations of conjugated paracetamol were found between the 2 groups. Pretreatment with paracetamol did not influence the urinary excretion of free paracetamol but caused some shift in the urinary excretion of paracetamol conjugates: pretreated rats excreted 23% less of the paracetamol glucuronide and sulfate and 33% more of the paracetamol mercapturate than the control animals. A depression of the microsomal mixed-function oxidase activity is presumed to be the main cause of the paracetamol-induced protection against paracetamol hepatotoxicity.
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PMID:Studies on the mechanism of paracetamol-induced protection against paracetamol hepatotoxicity. 47 30

The administration of the antioxidant, butylated hydroxytoluene (BHT) to rats decreased the utilization of [2-14C]orotic acid for the synthesis of cytidine nucleotides in the acid-soluble extract and RNA of the liver. The specific activity of the uridine components was slightly decreased. The depression of the specific activity of the cytidine components depended on the dose of the drug. Simultaneously preformed [U-14C]cytidine in experimental rats was to a higher degree transported to the liver and incorporated into RNA cytosine; its deamination was markedly suppressed. Both phenomena depend on the BHT dose. The concentration of both the uridine and the cytidine components of the acid-soluble extract remained unaffected by the administration of BHT. The utilization of [2-14C]orotic acid for the synthesis of DNA cytosine was depressed after the administration of BHT; by contrast, the specific activity of DNA thymine was higher. The incorporation of [1-14C]palmitic acid into microsomal phospholipids was not substantially influenced over the dose range 25--500 mg BHT/kg. The specific activity of neutral lipids in microsomes increased.
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PMID:Alterations in metabolism of cytidine components in rat liver after oral administration of butylated hydroxytoluene (in vivo study). 53 68

This working paper summarizes the known ultrastructural and biochemical effects of lead, mercury, cadmium, and arsenic on subcellular organelle systems following in vivo administration. Documented metal-induced alterations in nuclear, mitochondrial, microsomal, and lysosomal functions are discussed in relation to their potential impact on cellular responses to other environmental agents. Each of the above elements has been found to interfere with normal cellular replication and genetic processes. Mitochondrial swelling and depression of respiratory function are discussed in relation to known metal-specific perturbations of mitochondrial heme biosynthetic pathway enzymes. Inhibition of microsomal enzyme activities and protein synthesis by lead and mercury is compared to the apparent absence of such effects following arsenic or cadmium exposure. Lysosomal uptake of all the metals is documented, but biochemical alterations in these structures have been reported for only mercury and cadmium. It is concluded that these toxic metals are capable of interacting with, and biochemically altering major cellular systems at dose levels below those required to produce signs of overt metal toxicity. The impact of these effects on cellular response to other metals and xenobiotics in complex exposure situations is presently unknown, and further research is urgently needed in this area.
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PMID:General subcellular effects of lead, mercury, cadmium, and arsenic. 64 90

1 Pretreatment of rats with intraperitoneal injections of lead was shown to result in a depression of the microsomal mixed function oxidase system, as assessed by a decrease in hepatic microsomal P-450 and b5 content and by a decrease in the activity of the enzymes aniline hydroxylase and aminopyrine demethylase. Lead had a more marked effect on cytochrome P-450 than b5. 2 The activity of the rate-limiting enzyme of haem biosynthesis, delta-aminolaevulinic acid synthase, was inversely correlated with the microsomal cytochrome P-450 content. 3 The activity of the haem biosynthetic enzymes delta-aminolaevulinic acid dehydratase, coproporphyrinogen oxidase and ferrochelatase were decreased by increasing lead pretreatment. 4 The activity of the haem catabolic enzyme, haem oxygenase, was increased by lead pretreatment.
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PMID:Hepatic drug metabolism and haem biosynthesis in lead-poisoned rats. 65 97

The defect in myelinogenesis present in the Quaking mutant mouse was investigated using a double radioisotope technique for comparing the incorporation of amino acid into myelin proteins of normal and mutant mice. Quaking mice and littermate controls received intracranial injections of 150 muCi [3H]glycine and 25 muCi of [14C]glycine respectively. After 2 h their brains were combined and jointly processed to obtain subcellular fractions. The 3H/14C ratio for the myelin subfraction was 1.88 as compared to a 3H/14C ratio of 3.0 for the other subfractions, indicating a 40% decrease in glycine incorporation into myelin of Quaking mice. Myelin proteins were separated by discontinuous gel electrophoresis in the presence of sodium dodecyl sulfate (SDS) and the 3H/14C ratios determined in each gel slice. In contrast to the microsomal subfractions which gave a 3H/14C ratio of 2.6 across the gel, the 3H/14C ratio of myelin showed large variations with values ranging from 0.54 for proteolipid protein to 2.0 for some of the high molecular weight proteins. During development, the Quaking mutant exhibited a preferential depression in glycine incorporation into proteolipid protein in 18-day-old mice, while in older animals (32-54 days) the fast migrating basic protein, as well as the proteolipid protein, was labeled to a significantly lesser extent.
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PMID:Evidence for defective incorporation of proteins in myelin of the quaking mutant mouse. 83 36

Depression of the hepatic microsomal enzyme system(s) in adjuvant-induced polyarthritis (AIP), a chronic inflammation model, has been confirmed indirectly by the enhancement of hexobarbital Na-induced sleeping time and extended for the first time to zoxazolamine-induced paralysis. In addition, barbital Na-induced anesthesia was increased during the course of AIP development, indicating that the CNS of these rats appears to be more sensitive to drug effects, since this barbiturate is excreted virtually unmetabolized. Most likely because of these effects, LD50 values for acetylsalicylic acid, phenylbutazone and indomethacin in AIP rats decreased in terms of mg/kg (increased toxicity) as the disease became more severe (Day 21) since they are known ultimately to be metabolized by the liver. On the other hand, the toxicity of a new non-steroidal anti-inflammatory agent, meseclazone, was not altered significantly in AIP. This is most likely due to the fact that its near total conversion to 5-chlorosalicylic acid has been shown to occur by hydrolytic cleavage as it pases through the intestinal wall with litter hepatic involvement. Finally, carrageenan edema, a model of acute inflammation, did not affect barbiturate sleeping times of zoxazolamine paralysis, nor were any of these drugs studied more lethal in this disease state.
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PMID:Alteration of Hepatic microsomal enzyme systems and the lethal action of non-steroidal anti-arthritic drugs in acute and chronic models of inflammation. 89 77

In these studies the effects of ingested arsenic (As(+5)) on hepatic heme biosynthetic capability and hemoprotein function in adult male rats were investigated. Animals exposed for 6 weeks to 0, 20, 40, or 85 ppm sodium arsenate in the drinking water suffered depression of hepatic delta-aminolevulinic acid (ALA) synthetase and heme synthetase (ferrochelatase) activities, with maximal decreases to 67 and 55% of control levels, respectively, at 85 ppm. Concomitantly, urinary uroporphyrin levels were elevated by as much as 12 times, and coproporphyrin by as much as 9 times, control values. The rate of incorporation of (3)H-ALA into mitochondrial and microsomal hemes was depressed by 40-50% at 20 ppm but was increased with regard to controls by as much as 150% at the higher treatment levels. A similar biphasic pattern was observed in regard to (14)C-leucine incorporation into cellular membranal proteins. In contrast, the levels of ALA dehydratase, uroporphyrinogen I synthetase, aminopyrine demethylase, and cytochrome P-450 were not significantly changed in As(+5)-treated rats. These results support the hypothesis that chronic, low level, arsenic exposure results in selective inhibition of mitochondrial-bound heme biosynthetic pathway enzymes (ALA synthetase and heme synthetase) resulting in a substantial increase in urinary porphyrins, uniquely characterized by a greater increase in uroporphyrin than coproporphyrin levels. These changes occur independent of, or prior to, alterations in hepatic hemoprotein-dependent functions and may thus serve in the clinical analysis of pretoxic exposure to arsenic compounds in human populations.
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PMID:Effects of chronic arsenic exposure on hematopoietic function in adult mammalian liver. 90

Dietary protein deficiency is known to modify the response to the pharmacotoxicological activities of drugs and foreign compounds, due in part to altered rates of metabolism. Prediction of whether in vivo susceptibilities to foreign compounds are increased or decreased in protein deficient animals has been said to be related to the relative toxicites of the metabolic products. We have shown that weanling rats fed semipurified casein diets for 15 days show a 75% depression of hepatic microsomal mixed function oxidase activities. About one-fourth of this decrease is due to a retardation of the normal rate of liver cell proliferation and less microsomal protein; the remaining three-fourths is due to a reduction of the specific enzyme activity. This latter decrease is closely correlated with similar decreases in cytochrome P-450 and cytochrome c reductase activities and cytochrome P-450 contents. Although protein deficiency affects the relative contents of phosphatidylcholine and cytochrome P-450, this does not result in modifications of the Km for metabolism, as is seen with phenobarbital administration in the various dietary groups. The depression of mixed function oxidase enzyme activities caused by feeding the protein deficient diet for 15 days can be restored to normal by feeding the 20% casein diets for an additional 30 days in the case of aniline hydroxylase but only partially in the case of ethylmorphine N-demethylase. The complexities of determining the role of metabolism as a modulator of protein deficiency effects on foreign compound toxicity are discussed.
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PMID:The effect of quantity and quality of dietary protein on drug metabolism. 97 91

Mitochondrial and heavy microsomal fractions were isolated from rat hearts perfused for different intervals with Ca2+-free medium, as well as from hearts reperfused with control medium after perfusion with Ca2+-free medium. Contractile failure due to intracellular calcium deficiency produced by perfusing the isolated rat hearts with Ca2+-free medium resulted in a marked decline of calcium binding and uptake activities of the mitochondrial fraction without any effect on the microsomal fraction. On the other hand, inability of the rat hearts to recover their contractile force due to intracellular calcium overload produced by reperfusion for 10 min with control medium after 5-20 min of perfusion with Ca2+-free medium was associated with decreased microsomal calcium-binding and uptake activities and increased mitochondrial calcium-binding and uptake activities. When the hearts perfused with Ca2+-free medium in the presence of low sodium (35 mM) for 5 min were reperfused with control medium, the contractile force recovered completely, and appreciable augmentation in mitochondrial calcium transport or depression in microsomal calcium transport as seen in conditions of intracellular calcium overload did not occur. These results suggest dramatic alterations in calcium-transporting properties of mitochondria and sarcoplasmic reticulum in hearts failing due to intracellular calcium deficiency and calcium overload, respectively.
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PMID:Subcellular calcium transport in failing hearts due to calcium deficiency and overload. 98 2

The nuclear volumes were measured in the central, intermediate and peripheral zone of the classic liver lobule of adult male albino rats exposed to ether anaesthesia lasting 15, 40 and 80 min. Related to control animals there was a significantly lower nuclear size after a 40 min duration of narcosis and a significant higher volume after 80 min in the central part of the lobule. With a slight but not significant decrease of nuclear volume in the intermediate zone after 15 min and a significant increase after 80 min respectively, the peripheral lobular region constantly showed significantly smaller nuclei. But here, too, a disappearance of decrease was recorded after 80 min. The interpretation of the data is based upon a typical distribution of cell organelles, enzymatic pathways, and metabolites in the different zones of the hepatic lobule. The intensity of reaction and appearance of diminution in nuclear volume, indicating a functional depression and probably accentuated by a circular dependent low O2-tension of tissue, is interpreted in connection with different local concentrations of ether. An improvement of the blood flow by augmental local metabolites and an increased arterial influx presumably support the recovery and favour a concentration-dependent induction of microsomal enzymes in the central part of the lobule especially.
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PMID:[Investigation on the morphokinetic reactions of the rat liver to ether anaesthesia of different length (author's transl)]. 98 76


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