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)

The effects of administering indole-3-carbinol (I-3-C) on carbon tetrachloride (CCl4)-induced hepatotoxicity were examined. Mice received by gavage 0-150 mg I-3-C/kg body wt in methanol-extracted corn oil, followed 1 h later by 15 microliters CCl4/kg body wt in corn oil. Animals were sacrificed 24 h after receiving CCl4. Pretreatment with I-3-C reduced the degree of centrolobular necrosis, as observed histologically. Additionally, CCl4-mediated elevated serum enzymes were reduced by I-3-C. Although I-3-C induced elevated levels of cytochrome P-450 and associated mixed-function oxidase activity, the CCl4 depression of these parameters was not clearly reversed by I-3-C. However, CCl4 produced decreases in hepatic levels of glutathione (GSH), total reducing equivalents, and protein sulfhydryls, all of which were restored to control levels by I-3-C. Using mouse liver microsomes in an NADPH-fortified reaction mixture, I-3-C inhibited, in a concentration-dependent manner, CCl4-initiated lipid peroxidation, with 50% inhibition at 35-40 microM I-3-C. When mice were treated by gavage with 50 mg [14C]I-3-C/kg body wt, concentrations of radiolabel in the liver were greater than 100 microM after 1 hr. This was five times the level of radioactivity measured in blood and three times the concentration of I-3-C necessary for 50% inhibition of CCl4-mediated lipid peroxidation in vitro. The data are consistent with the hypothesis that I-3-C intervenes in CCl4-mediated hepatic necrosis by combining with reactive free radical metabolites of CCl4, thereby protecting critical cellular target sites.
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PMID:Protection against carbon tetrachloride hepatotoxicity by pretreatment with indole-3-carbinol. 355 31

To explore which rat liver cytochrome P-450 species are involved in aldrin epoxidation, we have studied the catalytic activities of a series of cytochrome P-450 isozymes purified from untreated and inducer-treated Sprague-Dawley rats. Of ten cytochrome P-450 forms analyzed, seven isozymes, listed in order of decreasing activity, catalyzed aldrin epoxidation: P-450UT-A, P-450PB-C, P-450UT-H, P-450PB-B, P-450PCN-E, P-450UT-F, and P-450PB-D. P-450UT-I, P-450BNF-B, and P-450ISF-G were not very active at all. A novel aldrin metabolite, endo-dieldrin, was formed by cytochrome P-450UT-F in a 6-fold excess over dieldrin, which is the exo-isomer. The activity of aldrin epoxidase furthermore was assayed in liver microsomes from Sprague-Dawley rats of diverse physiological status and after pretreatment with various inducers resulting in a peculiar pattern of cytochrome P-450 isozymes. Untreated animals, at an age of 3 weeks, showed similar enzyme activities in both genders. During maturation, the activity of males increased by 3-fold, while the activity in females did not significantly change during this period. Pretreatment with pregnenolone-16-alpha-carbonitrile or dexamethasone strongly increased the activity in females. Pretreatment with dexamethasone did not increase the activity of males. A 50% depression of epoxidase activity was noted for males pretreated with 5,6-benzoflavone. Phenobarbital pretreatment increased the activity of females by 12-fold and of males by 2-fold. Males responded to pretreatment with polychlorinated biphenyls in a strain dependent fashion: enzyme activity was increased 2-fold in Sprague-Dawley rats but was not altered in Wistar rats. "Theoretical" values of microsomal epoxidase activity were calculated for weanling and adult Sprague-Dawley rats from turnover numbers and published data on the relative abundance of aldrin epoxidizing P-450 isozymes (Waxmann et al., Biochemistry 24, 4409, 1985). These values agreed with the activities determined. A similar statement can be made for male rats of both strains pretreated with inducers, when the ratio of enzyme activity of pretreated to control animals was used as a basis of comparison. The activity ratio of females pretreated with pregnenolone-16-alpha-carbonitrile, dexamethasone and phenobarbital, however, was much higher than the ratio calculated. Our results reveal that aldrin epoxidation is a reaction indicative of male specific and of phenobarbital-inducible cytochrome P-450 isozymes in rat liver.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Rat liver cytochrome P-450 isozymes as catalysts of aldrin epoxidation in reconstituted monooxygenase systems and microsomes. 360 56

The experiments on rats have shown that alpha-tocopherol and lidocaine pretreatment leads to a decrease in the level of ischemic cell necrosis in the liver. The volume of cell necrosis in the liver was significantly decreased (more than threefold) in the case of drug pretreatment. The combination of alpha-tocopherol with lidocaine fully prevented the decrease in N-dimethylation of amidopyrine and cytochrome P-450 and b5 concentration, and the development of destructive alterations of cytoplasmic reticulum in the unaffected rat hepatocytes. alpha-Tocopherol and lidocaine pretreatment was effective for the retention of the depression of microsomal monooxygenases by phenobarbital in remote periods after acute hepatic ischemia.
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PMID:[Prevention, using alpha-tocopherol and lidocaine, of damage to the monooxygenase system activity and ultrastructure of hepatocytes following acute ischemia of the liver]. 368 56

Administration of a single intraperitoneal dose of 1,1-dichloroethylene (125 mg/kg, 1,1-DCE) to mice resulted in bronchiolar injury with selective necrosis of Clara cells. Degenerative changes were manifest in Clara cells as early as 1 h following 1,1-DCE exposure, and were characterized by marked swelling of mitochondria and aggregation of chromatin against the nuclear membrane. Cell death was apparent at 2 h; by 8 h, areas of the bronchiolar epithelium were devoid of lining cells, and at 24 h, the majority of Clara cells were exfoliated. The residual epithelium consisted of flattened cells which formed a thin lining for the airway. Necrosis of Clara cells early in the course of 1,1-DCE exposure coincided with peak covalent binding of [14C]1,1-DCE and significant depression of components of the pulmonary mixed-function oxidase system; cytochrome P-450 and aryl hydrocarbon hydroxylase activity were markedly reduced but not depleted. Liver damage involving centrilobular hepatocytes was observed at 24 h in 30% of treated animals, and coincided with significant inhibition of aryl hydrocarbon hydroxylase activity; cytochrome P-450 content, however, remained unchanged. While changes in the liver evoked by 1,1-DCE were less striking, the results in lung demonstrate positive temporal correlations between structural damage, peak covalent binding and disturbances of monooxygenase enzymes.
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PMID:Pulmonary toxicity of 1,1-dichloroethylene: correlation of early changes with covalent binding. 369 28

Treatment of mice and rats with polyriboinosinic acid-polyribocytidylic acid (poly I.C., 5 mg/kg i.p.), a potent interferon inducer, decreased hepatic cytochrome P-450 system content and activities without influencing P-450-independent xenobiotic metabolizing enzymes. Treatment with poly I.C. decreased the content of P-450 by 28% in mice (P less than 0.05) and 30% in rats (P less than 0.05) but did not alter the activity of cytochrome c reductase. With treatment of poly I.C., the activity of XO increased 87% in mice (P less than 0.01) and 30% in rats (P less than 0.01). Lipid peroxidation was enhanced by 82% in mice (P less than 0.01) and 95% in rats (P less than 0.05). These results raise the possibility that a part of the depression of P-450 system content and activities by poly I.C. might be caused by enhanced lipid peroxidation associated with increased activity of XO.
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PMID:Treatment with poly I.C. enhances lipid peroxidation and the activity of xanthine oxidase, and decreases hepatic P-450 content and activities in mice and rats. 375 66

A novel aspect of the regulation of heme biosynthesis and cytochrome P-450 concentration in rat adrenals, as pertains to the repressive role of testosterone, is described. Also, the presence of a sex difference in the activities of delta-aminolevulinate (ALA) synthetase and heme oxygenase, as well as the concentrations of heme and cytochrome P-450 in the adrenal mitochondrial and the microsomal fractions, are defined. The female rats displayed a nearly 2-fold higher value for the listed parameters. Castration of rats caused an elevation of ALA synthetase activity to approximate that of the female rats, whereas testosterone replacement depressed the enzyme activity to the level of the sham-operated animals. Moreover, female rats treated with testosterone showed a marked depression in adrenal ALA synthetase activity. This was accompanied by significant reductions in the mitochondrial and microsomal contents of cytochrome P-450 and heme. Heme oxygenase activity was neither altered by castration nor by the testosterone treatment of castrated and female rats. It is suggested that the adrenal ALA synthetase activity is regulated by plasma testosterone levels which, in turn, regulates the production of heme and the cellular levels of heme and cytochrome P-450. The mode of action of testosterone appears to be repressive in nature.
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PMID:Sex difference in adrenal heme and cytochrome P-450 metabolism: evidence for the repressive regulatory role of testosterone. 384 Feb 3

A novel effect of metal ions in the brain is described. Mn was found to alter heme metabolism and the cytochrome P-450-dependent mixed-function oxidase activities in rat brain. A more than 2-fold increase in benzo(alpha)pyrene hydroxylase and 7-ethoxycoumarin deethylase activities were observed in the brain of rats treated for 7 days with Mn. The increases were regionally distributed; the highest elevations were observed in the hippocampus, pons and the caudate putamen. Moreover, in rats treated with Mn for 1 or 7 days a marked depression in the activity of the mitochondrial ALA synthetase was observed. The activity of the microsomal heme oxygenase was also inhibited at 7 days, but not 1 day, after Mn treatment. These inhibitions were reflected in an initial decrease, followed by a rebound return to normal, in the concentration of cytochrome P-450 in the brain. Mn was ineffective in vitro in altering heme and drug metabolism activities. It is suggested that Mn-mediated alterations in heme metabolic activities promote changes in the composition of cytochrome P-450 species in the brain microsomal fractions, such that the relative concentrations of the molecular species which catalyse aryl hydrocarbon hydroxylase activity become selectively increased.
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PMID:Regulation of heme and drug metabolism activities in the brain by manganese. 392 Oct 22

Cyclophosphamide (CP) administration to rats in a single i.p. dose (200 mg kg-1), while producing urinary bladder toxicity and 30-40% depression of the hepatic microsomal mixed function oxidase (MFO), failed to produce any depression of MFO activities in extrahepatic tissues such as lung, kidney and intestine. Phenobarbital pretreatment of the rats, which is known to enhance hepatic microsomal activation of CP, protected against CP-induced urinary bladder toxicity and the depression of hepatic MFO activities. This protection appears to be, at least in part, related to phenobarbital induction of hepatic cytochrome P-450 isozyme(s) that metabolizes CP to a new metabolite tentatively identified as didechlorodihydroxycyclophosphamide.
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PMID:Effects of the induction of hepatic microsomal metabolism on the toxicity of cyclophosphamide. 396 72

At a high dose, cyclophosphamide (Cy, 200 mg/kg) causes depression of the enzyme activity of the hepatic mixed function oxygenase (MFO) system in Sprague-Dawley rats. The present report provides evidence for the early regeneration of the depleted enzyme activity in Cy-treated rats by purified protein A (P) of Staphylococcus aureus. Enzymes of the MFO system, such as aminopyrine demethylase and aryl hydrocarbon hydroxylase, were assayed and the content of cytochrome P-450 was determined. Inoculation of P (60 micrograms/kg) prior to Cy inoculation provides a better effect than P administration after Cy. The exact mechanism of P action is unknown. P-treated animals appear to have an ability to repair the damage caused by the toxic metabolites of Cy earlier than those in the Cy group. This property of protein A may become useful in accelerated regeneration of the enzyme activity in the hepatic MFO system following the toxic insult of Cy metabolites.
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PMID:In vivo protection by protein A of hepatic microsomal mixed function oxygenase system of cyclophosphamide-treated rats. 397 77

Experimental and more limited clinical studies have suggested that influenza vaccination may depress the oxidative hepatic metabolism of various drugs and lead to drug toxicity. The alleged mechanism is the formation of interferon and the resulting decrease in cytochrome P-450 available for drug oxidation. Because of the clinical and basic science implications of these reports, we undertook to study the effects of influenza vaccine on the metabolism of three commonly used drugs: chlordiazepoxide, theophylline, and lorazepam. Our healthy male subjects were studied just before and 1 and 7 days after vaccination. As expected, lorazepam metabolism, which proceeds by glucuronidation and not oxidation, was not altered by vaccination. Surprisingly, however, the oxidation of chlordiazepoxide was also not depressed by the vaccine. Theophylline oxidation, which proceeds primarily by microsomal oxidation (demethylation), was significantly decreased 1 day, but not 7 days, after vaccination. Serum alpha-interferon levels rose after vaccination for only about 8 hours, and levels of gamma-interferon rose to about 500 IU/ml at 24 hours, peaked at 72 hours, and returned to normal by 100 hours after dosing. It appeared that the higher the theophylline clearance before vaccination, the greater the degree of clearance depression after vaccination. Thus the inhibition of drug oxidation after influenza vaccination is selective and each drug should be studied individually. The degree of depression of theophylline clearance is small and transient and appears to be greater in subjects with higher prevaccination clearance.
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PMID:Effects of influenza virus vaccine on hepatic drug metabolism. 397 1


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