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)

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

Effects of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) on the hepatic mixed-function oxidase system in male rats were studied both in vivo and in vitro. A single dose of CCNU (40 mg/kg) caused a significant reduction in hepatic mixed-function oxidase activities within 3 days after administration. The depression was prolonged for cytochrome P-450, total haem and the metabolism of several type I substrates lasting up to 10 weeks after a single dose. By contrast, aniline hydroxylase, cytochrome b5 and NADPH-cytochrome c reductase activities returned to near control levels after week two. Microsomal enzymes in the kidneys of treated animals however, were unaltered. Serum glutamic pyruvic and glutamic oxaloacetic transaminase and bilirubin levels, indicators of hepatotoxicity, were greatly elevated 3 days after CCNU treatment. These parameters fell rapidly but were still above control levels to the end of the 10-week study. When added in vitro, CCNU reduced apparent cytochrome P-450 content and the metabolism of type I substrates in microsomes from untreated, phenobarbital (PB) and 3-methylcholanthrene (3-MC)-pretreated rats. Total haem and NADPH-cytochrome c reductase were not affected whereas aniline hydroxylase activity was activated. CCNU interacted with hepatic microsomes to produce a type I difference spectrum.
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PMID:Interaction of the oncolytic drug, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea with the mixed-function oxidase system in rats. 672 31

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

A pronounced and irreversible depression of the erythroid and liver delta-aminolevulinate dehydratase (porphobilinogen synthase; 5-aminolevulinate hydro-lyase, EC 4.2.1.24) activity was observed in rats exposed to trichloroethylene, a widely used solvent. The depression could not be restored after the treatment with dithiothreitol and zinc; however, radioimmunoassay of delta-aminolevulinate dehydratase indicated that trichloroethylene exposure did not essentially decrease the amount of enzyme. The depression of the enzyme activity thus proved to be due not to a reduction in the enzyme amount but to enzyme inhibition. The purified holoenzyme (fully activated delta-aminolevulinate dehydratase with 1 atom zinc per subunit) and apoenzyme (fully activated enzyme with the remaining zinc less than 0.1 atom per subunit) were prepared to investigate the in vitro inhibition of the enzyme by trichloroethylene. Incubation with trichloroethylene did not inhibit the holoenzyme, but inhibited the apoenzyme dose-dependently. Trichloroethylene inhibited the holoenzyme when incubated with the mixed function oxidase system. The in vitro experiments reported here indicate two mechanisms of the enzyme inhibition by trichloroethylene. In the liver of rats exposed to trichloroethylene, cytochrome P-450 concentration and heme saturation of tryptophan pyrrolase (EC 1.13.11.11) are reduced; in addition, the activity of delta-aminolevulinate synthase (EC 2.3.1.37) increased. After exposure to trichloroethylene at 2.14 g/m3, urinary delta-aminolevulinic acid increased to 142% of the control, while the excretion of coproporphyrin was reduced to 19.6% of the control.
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PMID:Inhibition of delta-aminolevulinate dehydratase in trichloroethylene-exposed rats, and the effects on heme regulation. 674 80

In the rat testis, 7 days after hypophysectomy, the microsomal content of cytochrome P-450 decreased to a negligible level. The sodium dodecyl sulfate gel electrophoresis of the microsomal preparation did not reveal a decrease in apocytochrome P-450; however, in this preparation, heme was undetectable. The latter did not reflect decreases in the activities of the heme biosynthesis enzymes. Also, an increase in heme oxygenase activity did not appear responsible for the suppression of the cytochrome levels. The cellular basis for the depression of the cytochrome was explored by measuring the incorporation of [14C]delta-aminolevulinate into the testicular microsomal and mitochondrial hemoproteins, and determining the relative affinity of microsomal heme for the endoplasmic reticulum membranes. In comparison with the sham-operated animals, in hypophysectomized rats, the specific 14C activity of heme in mitochondrial fraction was not decreased; however, that of the microsomal fraction was markedly reduced. The latter appeared to reflect a lowered binding affinity of the apoprotein moiety of cytochrome P-450 for heme. The treatment of hypophysectomized rats with human chorionic gonadotropin partially restored the normal level of the cytochrome. It is suggested that the anterior pituitary hormones control the level of cytochrome P-450 in the testis through factors which do not involve the production of heme; rather, the control appears to involve the processes of assembly of the hemoprotein and the association of the heme molecule with the apoprotein.
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PMID:Dissociation of heme metabolic activities from the microsomal cytochrome P-450 turnover in testis of hypophysectomized rats. 674 60

The effects of long-term chronic ascorbic acid deficiency and excessive ascorbic acid consumption on bile acid metabolism and biliary lipid composition were studied in guinea pigs. Male, weanling guinea pigs were fed a cereal-based scorbutigenic diet for 19 or 21 weeks. Ascorbic acid was administered either orally at 0.15 (group A) or 2.0 (group B) mg/100 g body weight, or it was mixed in the diet at levels of 500 (group C), 16-22 (group D), or 20,000 mg/kg (group E). Chronic ascorbic acid deficiency (groups A and D) caused depression of hepatic cytochrome P-450 levels and elevation of plasma cholesterol. Excessive ascorbate consumption did not alter these parameters relative to control levels. In contrast to results obtained in guinea pigs fed low or high amounts of ascorbate for 7-9 weeks, prolonged consumption of inadequate or excessive ascorbate resulted in little or no change in bile acid metabolism and biliary lipid composition except that bile acid pool size was increased 12% as a result of excessive ascorbate ingestion. Results of the present study suggest that there may be important differences in the guinea pig's metabolic response to ascorbic acid deficiency and ascorbic acid excess, depending on the length of the experimental period.
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PMID:Long-term effects of inadequate and excessive dietary ascorbate on bile acid metabolism in the guinea pig. 674 20

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

Depletion of hepatic glutathione leads to an increase in lipid peroxidation and depression of cytochrome P-450-catalyzed metabolism of the azo dye carcinogen, N,N-dimethyl-4-aminoazobenzene. This contributes to the marked decrease in biliary excretion of N-demethylated metabolites of the dye. Parallel time courses are seen for decreased hepatic glutathione, enhanced lipid peroxidation and depressed excretion of dye metabolites. In vitro metabolism of DAB by hepatic 10,000 g supernatant fractions is depressed by iron only after glutathione depletion. In view of the iron requirement for microsomal lipid peroxidation, it is proposed that glutathione depletion leads to an increase in the intracellular iron available for activation of lipid peroxidation. In this way, glutathione may contribute to the regulation of cytochrome P-450 activity.
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PMID:Glutathione, lipid peroxidation and regulation of cytochrome P-450 activity. 681 17

The induction and passive transfer of interferons have been shown to depress the level of cytochrome P-450 drug metabolism system of liver microsomes. Inducers of alpha or beta (Type I) interferons, such as Tilorone-HCl, statalon, mengovirus and others, suppressed the cytochrome P-450 system of rats or mice after administration. Induction of gamma (Type II) interferon also resulted in depression of the cytochrome P-450 system of mice. The gamma interferon was induced by sensitization of mice with Mycobacterium bovis strain BCG followed by challenge with tuberculin. The degree of depression of the cytochrome P-450 system correlated with the levels of interferon induced. In addition, passive transfer of exogenous gamma interferon also resulted in depression of the murine cytochrome-450 system. The metabolism of diphenylhydantoin, a drug metabolized by cytochrome-450, was examined in mice in which gamma interferon was induced. The metabolism of diphenylhydanoin was severely inhibited in mice which interferon was induced, and the level of inhibition correlated with the titer of gamma interferon induced. Passive transfer of gamma interferon also depressed the metabolism of diphenylhydantoin by murine cytochrome P-450.
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PMID:Effects of interferon on drug metabolism. 681 39


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