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)

Adriamycin treatment in vivo or addition to incubation mixtures in vitro inhibits hepatic drug metabolism. It has been suggested that adriamycin-induced membrane lipid peroxidation may be a mechanism responsible for this activity in vitro. To determine if similar mechanisms operate in vivo, adriamycin inhibition of drug metabolism was compared in rats whose tissue lipid peroxidizability was altered by manipulating dietary levels of vitamin E. Weanling rats maintained on vitamin E deficient (0 ppm) or supplemented (10 or 100 ppm) diets for 12 weeks were given either adriamycin, 5 mg/kg/week, or equal volumes of the saline vehicle for 3 weeks intraperitoneally. Vitamin E deficiency alone (0 ppm, saline pretreatment) produced a 37% increase in hepatic lipid peroxidation without any appreciable alteration in hepatic aniline hydroxylase, ethylmorphine N-demethylase or aryl hydrocarbon hydroxylase activities. Adriamycin pretreatment altered hepatic lipid peroxidizability over corresponding saline pretreated controls dependent on dietary vitamin E. No increase was seen in the 100 ppm group, while 44% and 500% increases occurred at 10 and 0 ppm vitamin E, respectively. Adriamycin pretreatment decreased drug-metabolizing enzyme activity by an average of 32% for aniline hydroxylase, 26% for ethylmorphine N-demethylase and 63% for aryl hydrocarbon hydroxylase. Statistically, decreases in drug metabolism were independent of dietary vitamin E and did not correlate with lipid peroxidizability. These data would suggest that in vivo adriamycin-induced depression of hepatic drug-metabolizing enzymes is not mediated by elevated lipid peroxidation.
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PMID:Increasing lipid peroxidation by vitamin E deficiency does not augment adriamycin-induced inhibition of hepatic drug metabolism. 665 95

The pyrrolo(1,4)benzodiazepine antitumor antibiotic, anthramycin, shares a number of toxicities with the widely used anticancer agent adriamycin. We investigated whether acute doses of anthramycin and the structurally related compounds, sibiromycin and tomaymycin, would depress P-450-dependent drug biotransformations as has been reported for adriamycin. Alterations in drug metabolism rates were determined in rats using 50 and 75% of the approximate 7-day LD50 determined in mice. 4 days post dosing ethylmorphine demethylase and aniline hydroxylase activities in liver 9000 g supernatant were depressed from 26 to 76%. Tomaymycin lowered drug metabolism in a dose-related manner, while sibiromycin produced the greatest amount of depression. Like adriamycin, the pyrrolo(1,4)benzodiazepines possess the ability to depress hepatic drug metabolism and therefore may affect the disposition of compounds with which they are co-administered.
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PMID:Acute treatment with pyrrolo(1,4)benzodiazepine antitumor antibiotics alters in vitro hepatic drug metabolizing activity in rats. 668 84

This paper describes the effects of the interferon inducing agents tilorone and polyriboinosinic acid . polyribocytidylic acid (poly IC) on the postnatal development of hepatic cytochrome P-450-linked monooxygenase systems of male rats from birth through early adolescence. The administration of tilorone to rats on days 1 and 2 postpartum modified the changes in the activities of hepatic monooxygenase systems that occur normally during the first four days postpartum. Thus, aniline hydroxylase activity, which develops very rapidly during the first 2 days postpartum, was depressed markedly by tilorone, ethylmorphine N-demethylase activity was depressed moderately, and benzo[a] pyrene hydroxylase, normally the slowest of the three monooxygenase activities to develop, was induced. These changes in monooxygenase activities occurred without a significant change in the cytochrome P-450 content. These observations suggest that not all species of neonatal cytochrome P-450 are affected equally by tilorone administration. By day 7 postpartum, the cytochrome P-450 content and all three monooxygenase activities were depressed in rats that had received tilorone on days 1 and 2 postpartum. All three monooxygenase systems were depressed by the administration of a single dose of poly IC (10 mg/kg) in 1-, 2-, 21-, 28- and 56-day-old rats. The length of the period between maximal depression and complete recovery of cytochrome P-450 systems was shown to be a function of the age of the rat; it increased from about 6 hr in 1-day-old rats to 48 hr in 56-day-old rats. Protein is synthesized more rapidly and degraded more slowly in neonate than in adult animals; this may account for the more rapid recovery of poly IC-induced depression of monooxygenase systems in neonates.
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PMID:Effects of the interferon inducing agents tilorone and polyriboinosinic acid . polyribocytidylic acid (poly IC) on the hepatic monooxygenase systems of the developing neonatal rat. 671 32

Administration of a single dose of the potent interferon inducer poly rI:rC to Swiss Webster mice depressed hepatic cytochrome P-450 to 75% of control, ethylmorphine N-demethylase to 56% of control and DMN N- demethylases I and II to about 80% of control. Although each enzyme responded in a unique manner, maximum depression occurred at 24 hours after poly rI:rC administration and the concurrent administration of inhibitors of protein synthesis (actinomycin D or cycloheximide) prevented this depression. These data suggest that poly rI:rC effects on the mixed function oxidases are not species specific although depression follows a time course shorter than that reported in the rat (maximum depression at 40 hours after poly rI:rC administration) and that depression occurs through the stimulation of a protein responsible for degrading cytochrome P-450.
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PMID:Inhibition of polyriboinosinic:polyribocytidylic acid-induced depression of mouse hepatic mixed function oxidases by actinomycin D or cycloheximide. 673 4

The levels of cytochrome P-450, cytochrome b5, aminopyrine N-demethylase, and benzo[a]pyrene hydroxylase were depressed in hepatic microsomes following treatment of mice with the interferon inducer poly rI.rC. The decrease in the hepatic mixed function oxidase system was accompanied by an increase in the incorporation of amino acids into total microsomal protein. Fractionation of solubilized microsomes using a Sephacryl S-200 gel filtration column demonstrated that the increase in amino acid incorporation tended to be associated with proteins with molecular weights under 67 000. The fractions which contained cytochrome P-450 were further separated using a DEAE cellulose column. The amount of labelled amino acids associated with the cytochrome P-450 fractions was uniformly depressed in preparations from poly rI.rC treated animals compared with saline-treated controls. These results suggest that poly rI.rC causes a depression in the rate of synthesis of the apoprotein of cytochrome P-450 while increasing the incorporation of amino acids into other hepatic proteins. The decrease in apocytochrome P-450 synthesis explains the marked loss of drug biotransformation which occurs following induction of interferon.
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PMID:Inhibition of the synthesis of hepatic cytochrome P-450 by the interferon-inducing agent poly rI.rCi. 673 84

One of the serious toxicities of cyclophosphamide chemotherapy is urotoxicity. In addition to causing leukopenia, high-dose cyclophosphamide caused both depression of hepatic microsomal enzyme activities and extensive urinary bladder damage, suggesting that a common biochemical mechanism may be responsible for both of these effects. Administration of 180 or 200 mg cyclophosphamide per kg to Wistar rats caused 41 to 67% decrease in aryl hydrocarbon hydroxylase activity, a 21 to 54% decrease in aminopyrine demethylase activity, and a 34 to 40% decrease in cytochrome P-450 content. This dose of cyclophosphamide also caused hematuria as well as necrosis and edema in the urinary bladder. Administration of N-acetylcysteine or sodium-2-mercaptoethane sulfonate (mesnum) with cyclophosphamide, while not protecting against leukopenia, protected against the enzymatic inactivation and urotoxicity. The biochemical basis of these observations is discussed. The results suggest that a common metabolite of cyclophosphamide, most probably acrolein, is responsible for both of these undesirable effects of cyclophosphamide therapy. Use of combinations including cyclophosphamide and an appropriate thiol may increase the therapeutic index of this drug.
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PMID:Protective role of thiols in cyclophosphamide-induced urotoxicity and depression of hepatic drug metabolism. 680 12

Because of previously reported hepatic abnormalities in burns, the activity of the hepatic drug metabolizing system was assessed in burned Sprague-Dawley rats. In 16% burned male rats, pentobarbital sleeping times were significantly prolonged from day 1 to day 24 postburn, and trichloroethanol sleeping times were significantly prolonged from day 1 to day 10 postburn. The activity of p-nitroanisole O-demethylase was significantly depressed in male rats at 5, 10, and 17 days post-16% burn. In female rats, this enzyme was more depressed at 10 days post-16% burn than in male rats. A direct relationship was found between per cent burn and impairment of enzyme activity. The depression of drug metabolizing enzymes was inducible by phenobarbital pretreatment. Pretreatment with the immunosuppressive drug azathioprine prevented the enzyme depression at 5 days postburn, a result which possibly implicates a postburn hyperimmune response as the mechanism for the depressed enzyme levels.
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PMID:The effect of thermal injury on drug metabolism in the rat. 686 44

Various parameters of haem and drug metabolism were measured during the course of liver regeneration after two-thirds hepatectomy. Partial hepatectomy produced a significant depression in delta-ALA synthetase and delta-ALA dehydratase, and induction in haem oxygenase at an early stage of regeneration. The values returned to normal within 7-14 days. These changes were also accompanied by a marked decline in benzo(a)pyrene hydroxylase and aminopyrene demethylase. The level of glutathione and the activity of glutathione reductase also increased during the early stage of proliferation. The increased level of glutathione with concomitant decrease in drug-metabolizing enzymes and induction in haem oxygenase could be considered as a protective mechanism for the detoxication process, although a contribution from other biotransforming mechanisms cannot be excluded.
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PMID:Haem and drug-metabolizing enzymes in regenerating rat liver. 689 99

The frequency of gram-negative infections and endotoxemia in the perinatal period prompted an investigation of the effects of endotoxin (Escherichia coli 026B6) on hepatic drug metabolism. Gravid female rats given injections IP with different dosages of lipopolysaccharide during late pregnancy resulted in significant depression of the liver microsomal cytochrome P-450 dependent monooxygenase activities. The acute administration of endotoxin to mothers (1.4 mg/kg on seventh day after parturition) significantly decreased the hepatic activity of aminopyrine demethylase and contents of cytochrome P-450 of suckling neonates and mothers. However, chronic administration of endotoxin (0.2 mg/kg/day for 7 days) to lactating mothers did not alter neonatal enzyme activities. When neonates themselves were given injections of endotoxin (1.0 mg/kg) at 7, 16, and 27 days of age, a significant reduction in levels of mixed function oxidase enzymes was observed. These observations suggest that the ability of mothers and neonates to metabolize drugs is significantly decreased upon exposure to endotoxin, and this demands careful evaluation of drug disposition studies in gram-negative sepsis.
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PMID:Gram-negative endotoxin administration decreases hepatic drug-metabolizing enzymes during development in rats. 699 41

The effects of fenitrothion and methylparathion on the activities of cholinesterase and hepatic microsomal monooxygenases were investigated and compared following a single or repeated oral administration of an equimolar and low dose of the insecticides. The activities of cholinesterase in brain and plasma were inhibited equally by the repetitive administration of both insecticides. Aminopyrine N-demethylase activity and cyt.P-450 content were not affected under the same experimental conditions. However, methylparathion, when given repeatedly, inhibited the dearylation and desulfuration of it own. The results may indicate that low dose continuous exposure to methylparathion could cause the depression of its own metabolism in rat.
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PMID:Comparison of the effect of an equimolar and low dose of fenitrothion and methylparathion on their own metabolism in rat liver. 709 8


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