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)

Weanling male Sprague-Dawley rats were fed either a nutritionally complete synthetic diet (Diet 1) or a diet marginally deficient in choline and methionine, and lacking folacin (lipotrope deficient, Diet 2) to determine the role of hepatic mixed-function oxidase metabolism of aflatoxin B1 (AFB1) in the Diet 2-induced enhancement of AFB1 hepatocarcinogenesis previously reported. Hepatic microsomal mixed-function oxidase activities, as assayed by ethylmorphine N-demethylation, ethoxycoumarin O-dealkylation, cytochrome c reduction, AFB1 metabolism, and cytochrome P-450 content, were all depressed by Diet 2. Furthermore, the proportion of an i.p. dose of AFB (1 mg/kg) that became covalently bonded to DNA and RNA was similarly reduced when measured 6 hr after administration. The formation of AFB1-protein adducts was not influenced by dietary treatment. The depression of DNA and RNA adduct formation in the Diet 2 animals was probably related to the lower mixed-function oxidase activities and not to an alteration of glutathione levels, which remained unchanged by dietary treatment. These results suggest that the marginally lipotrope-deficient diet does not enhance tumor formation through an increased microsomal activation of AFB1. Alternative hypotheses without data are suggested.
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PMID:Dietary lipotropes, hepatic microsomal mixed-function oxidase activities, and in vivo covalent binding of aflatoxin B1 in rats. 8 78

The modifying effects of daily ethanol ingestion in the drinking water as a 15 % solution (v/v) on drug biotransformational changes induced by inhalation exposure to styrene (300 ppm or 1260 mg/m3, 6 h daily, 5 d/week, up to 17 weeks) were studied in rat liver and kidney. The drug hydroxylation activities (7-ethoxycoumarin O-deethylase and 2,5-diphenyloxazole hydroxylase) both in liver and in kidneys were increased more by ethanol ingestion than by styrene inhalation. When administered in combination, styrene and ethanol exerted mostly an additive enhancing effect. However, hepatic NADPH-cytochrome c reductase activity was reduced both in styrene and in ethanol-treated rats. Hepatic styrene oxide hydratase activity was virtually unaffected by styrene treatments. The depression of glutathione concentration in liver was greater after styrene-ethanol than after styrene treatment alone. The hepatic UDPglucuronosyltransferase activity was enhanced slightly both in styrene and in styrene-ethanol rats. The binding affinity of styrene towards cytochrome P-450 was increased after styrene inhalation as shown by lowered K8 values. The perirenal fat concentration of styrene showed a rough inverse relationship to the overall monooxygenation activities in liver and kidney. Despite the additively induced enzyme activities in styrene-ethanol-treated rats the accumulation of styrene in fat of these animals was on the whole somewhat greater, suggesting that these two solvents in vivo also have mutual inhibitory effects on biotransformation.
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PMID:Effects of intermittent styrene inhalation, ethanol intake and their combination on drug biotransformation in rat liver and kidneys. 11 16

A progressive depression in the in vitro hepatic microsomal enzyme metabolism of drug substrates, during pregnancy in the Wistar rat, was measured against various parameters. This depression was greatest with aniline para-hydroxylation and least with p-nitrobenzoic acid reduction. The depressed metabolism, which correlated with prolonged in vivo hexobarbital sleeping times, was paralleled by falls in hepatic microsomal cytochrome P-450 levels. There was a rapid reversal of this depression just before delivery, but these changes did not appear to be controlled by progesterone levels. The suggestion is advanced that the lower levels of hepatic microsomal enzyme activity might reflect a biological control mechanism to ensure the elevated levels of progesterone required to maintain the pregnant state. The relationship between changes in liver weight and enzyme activity was also examined as a possible explanation of the observed depression in drug metabolism during pregnancy.
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PMID:Hepatic microsomal metabolism of drugs during pregnancy in the rat. 24 12

Administration of N-nitrosodiethylamine (diethylnitrosamine, DEN) to mice caused a loss of cytochrome P-450 and a corresponding depression in the activities of aminopyrine demethylase and aniline hydroxylase. Maximum effects were achieved 24 hr. after a single dose of 100 mg/kg. In chronic experiments, similar effects were achieved after animals had been drinking water containing 50 ppm of DEN for 12 weeks. The effects of DEN on aminopyrine demethylase could not be reproduced by collecting microsomes, from homogenates which had been treated with DEN in vitro. Homogenates prepared from livers of mice treated chronically with DEN were used to activate compounds to mutagens in the Salmonella/microsome test of Ames. Activation by these homogenates was not lower than activation by homogenates prepared from control animals. In fact, activation of aflatoxin B1 was enhanced by use of homogenates from DEN-treated animals as source of activating enzymes.
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PMID:Effects of N-nitrosodiethylamine on murine hepatic mixed-function-oxidase activities. 36 84

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

1. Inhalation exposure of adult male rats to a mixture of 1,1,1-trichloroethane (500 p.p.m.) and trichloroethylene (200 p.p.m.) for four days 6 h daily resulted in an accumulation of 1,1,1-trichloroethane in perirenal fat. Further exposure on the fifth day caused a rapid increase in various organ contents of both solvents with secondary depression of brain RNA. 2. The four-day exposure doubled the RNA content of liver and caused a slight decline in the concentrations of glutathione in liver. 3. The amount of cytochrome P-450 in liver was increased, as well as the overall mono-oxygenase activity, measured with styrene as substrate. During continuing treatment on the fifth day, styrene mono-oxygenase activity decreased, the activity after 6 h being only about 50% of that at the beginning of the fifth day of exposure. 4. UDP-glucuronosyl transferase activity (measured in digitonin-activated microsomes) was doubled by the four-day combined exposure to 1,1,1-trichloroethane and trichloroethylene. 5. The changes during the fifth day of exposure, e.g. rapid increase in the concentrations of solvents in organs, the detection of trichloroethylene in tissues and depression of mono-oxygenase activity, obviously also occurred during the exposures on days 1 to 4 and reverted during each post-exposure period.
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PMID:Biochemical and toxicological effects of combined exposure to 1,1,1-trichloroethane and trichloroethylene on rat liver and brain. 65 14

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

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

The parathion analogue O, O-diethyl, O-phenyl phosphorothionate (SV1) is hepatotoxic when given in large intraperitoneal doses (400 mg/kg body weight) to male rats that have been treated previously with phenobarbitone. The lesion produced at 24 h after dosing is a periacinar hydropic degeneration which appears identical to that caused by carbon disulphide (CS2) in similarly pretreated rats. Both lesions are characterized by a marked depression in hepatic microsomal cytochrome P-450 levels, no change in the concentrations of Na+, K+ and Ca++ in liver water, in contrast to the periacinar necrogenic lesion caused by tccl4 in which Na+ and Ca++ levels markedly increase while that of K+ decreases. The similarity of the SV1 and CS2 induced liver changes, the fact that both chemicals undergo a similar oxidative desulphuration in the liver microsomes and that prior induction of the latter enzymes is necessary in order to produce the injury suggest a similar mechanism for both lesions. A reactive form of sulphur released from the metabolism of CS2 and phosphorothionates in the liver may become covalently bound to constituents of the endoplasmic reticulum of the liver cell and in this way initiate the toxic liver changes. Drugs and chemicals which contain P=S or C=S bonds and which undergo oxidative desulphuration in the liver could thus be similarly hepatotoxic.
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PMID:The hepatotoxicity of O,O-diethyl, O-phenyl phosphorothionate (SV1) for the rat. 126 38


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