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)

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

Interferon inducers, poly I:poly C, endotoxin, hepatic RNA, and Tilorone, were administered to rats at different time points in relation to the onset of hyperoxic exposure (O2 greater than 97%). All interferon inducers tested significantly reduced the mortality of rats when compared with the control groups. In hyperoxia alone, malondialdehyde, a product of lipid peroxidation, was significantly increased and the microsomal enzyme NADPH cytochrome c reductase decreased as measured in the whole lung. With the administration of either endotoxin or poly I:poly C these two parameters remained within the range of control values. These data suggest that the administration of interferon inducers protects against hyperoxic microsomal damage. After the administration of these interferon inducers with or without hyperoxia the increased activity of heme oxygenase and marked reduction of the heme content of microsomes were demonstrated. Since cytochrome P-450 and b5 are the major hemoproteins of microsomes and the known source of oxygen-free radical generation, the results obtained in this study appear to indicate that the depression of the hemoprotein of microsomes by the administration of interferon inducers may be largely responsible for the protective effects of these agents against hyperoxia.
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PMID:Protective effect of interferon inducers against hyperoxic pulmonary damage. 654 2

Exposure of rats to 0.1 and 0.5 mg Cd/kg subcutaneously (s.c.) thrice weekly for 5 weeks resulted in an accumulation of cadmium in the liver in concentrations of 40 and 95 micrograms/g tissue, respectively, and a microsomal burden of Cd amounting to approx. 2-3% of the retained cadmium. The cytoplasm contained about 80% of the cadmium. At an exposure dose of 0.1 mg Cd/kg, stimulation of lipid peroxidation by 22% and inhibition of ALA synthetase by 16% in the liver were observed. The higher exposure of 0.5 mg Cd/kg caused an inhibition of microsomal monooxygenase with depression of cytochrome P-450 and cytochrome b5 by 20% (over 2-fold prolongation of hexobarbital sleeping time and statistically significant decrease of activity of aniline p-hydroxylase). The loss of cytochrome P-450 probably was due to an intensified lipid peroxidation and induction of heme oxygenase (30% and 60% over control, respectively). Sequestration of cadmium by cytoplasm (metallothionein) does not protect microsomes against cadmium accumulation and specific biochemical disturbances.
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PMID:Stimulation of lipid peroxidation and heme oxygenase activity with inhibition of cytochrome P-450 monooxygenase in the liver of rats repeatedly exposed to cadmium. 654 50

The heme-cytochrome P-450 complexes represent sensitive metabolic systems for examining the biological impact of metals on important cellular functions. Many metals, both in the inorganic form and bound to organic moieties, potently induce heme oxygenase, the rate limiting enzyme of heme degradation. The resulting increase in the rate of heme breakdown is reflected in a marked depression of cellular cytochrome P-450 content and impairment of the oxidative metabolism of natural and foreign chemicals dependent on this hemeprotein. Organometal complexes do not mimic in all their aspects the actions of the inorganic elements which they contain. For example, organotins, in contrast to inorganic tin, produce a prolonged induction response of heme oxygenase in the liver but not in the kidney. Co-protoporphyrin is a much more potent inducer of heme oxygenase in liver than is inorganic cobalt; and Sn-protoporphyrin inhibits heme oxygenase activity nearly completely, whereas inorganic tin is a powerful inducer of the renal enzyme. Contrasting effects on heme metabolism exist as well within the metalloporphyrin species as demonstrated by the effects in vivo of Co-protoporphyrin and Sn-protoporphyrin on heme oxygenase activity; the former induces the enzyme whereas the latter potently inhibits it. In vitro, however, both compounds competitively inhibit heme oxidation activity. These differences, among others which characterize metal actions in vivo and in vitro attest to the importance of pharmacokinetic, adaptive and other host factors in defining the responses of the heme-cytochrome P-450 systems to the impact of metals in the whole animal.
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PMID:Control of heme and cytochrome P-450 metabolism by inorganic metals, organometals and synthetic metalloporphyrins. 654 1

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

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

Homosynaptic long-term depression (LTD) was studied in hippocampal slices from 12-18-d-old rats using field EPSP recording in the apical dendritic layer of CA1 pyramidal cells. Independent estimates of the alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) and the N-methyl-D-aspartic acid (NMDA) receptor-mediated components of the field EPSP were obtained in parallel using early and late measurements of a dual-component EPSP in a low-magnesium solution. LTD was induced by low-frequency stimulation (LFS; 2 Hz for 10 min), resulting in equal relative changes of the AMPA and NMDA receptor-mediated components. Under conditions when the AMPA receptor-mediated component was fully blocked, a similarly sized LTD was observed for the pure NMDA receptor-mediated EPSP (measured as initial slope or peak amplitude). Equal changes in AMPA and NMDA receptor-mediated components occurred also upon application of the adenosine agonist N6-cyclohexyladenosine (CHA), known to act by decreasing transmitter release. On the other hand, LTD was found to interact in a multiplicative manner with the presynaptic release changes induced by CHA and by paired-pulse facilitation. The induction of the LTDs of both AMPA and NMDA receptor-mediated EPSPs was blocked by the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid and by the phosphatase inhibitor okadaic acid. Partial blockade of LTD by okadaic acid resulted in equal partial blockade of the LTDs of the AMPA and NMDA receptor-mediated components. On the other hand, the L-type calcium channel blocker nifedipine, the metabotropic glutamate receptor antagonist (RS)-alpha-methyl-4-carboxyphenylglycine, the nitric oxide synthase inhibitor N omega-nitro-L-arginine, and the heme oxygenase inhibitor protoporphyrin IX zinc(II) had no effect on LTD of either the AMPA or the NMDA receptor-mediated component. These results of equal changes of AMPA and NMDA receptor-mediated components of the field EPSP in association with LTD, and the consistent parallelism of effects or noneffects on these components by various receptor antagonists and enzyme inhibitors, seem more easily explained by a presynaptic locus for LTD than by a postsynaptic one.
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PMID:On the linkage between AMPA and NMDA receptor-mediated EPSPs in homosynaptic long-term depression in the hippocampal CA1 region of young rats. 754 Jun 77

The heme oxygenase isozymes, HO-1 and HO-2, oxidatively cleave the heme molecule to produce antioxidants, the bile pigments, the gaseous cellular messenger, CO, and iron, a regulator of transferrin, ferritin, and nitric oxide synthase gene expression. HO-1 (hsp32) is a stress-inducible enzyme, whereas HO-2 is constitutively expressed at high levels in the testes and brain. In the present study, using immunohistochemical and in situ hybridization techniques, we report for the first time the cellular distribution of HO-1 and HO-2 in the testes of normal and heat-shocked rats and define a cell-specific expression of the isozymes and a stage-specific expression of HO-2 in the organ. In normal tissue, HO-1 was present at low levels in the Sertoli cells and could not be detected in germ or Leydig cells. HO-2, on the other hand, was most prominently expressed in residual bodies and was not detected in spermatogonia. Modest levels of HO-2 were observed in spermatocytes, spermatids, and select Leydig cells. In contrast, prominent expression of HO-2 messenger RNAs (mRNAs) was detected by in situ hybridization in spermatogonia, as well as spermatocytes, spermatids, and residual bodies of the seminiferous epithelium. The expression pattern of HO-2 protein and transcript in testes of heat-stressed (42 C; 20 min) rats did not differ from that in the control animals, whereas the expression pattern of HO-1 differed from that in the controls, in which distinct populations of Leydig and Sertoli cells displayed intense immunoreactivity. Thermal stress also resulted in an increase (2.8-fold) in the testicular HO-1 mRNA level within 1 h after treatment, followed by a significant increase (32%) in total microsomal heme oxygenase activity 6 h after treatment. Notably, this increase followed a significant depression (36%) in enzyme activity, which was detected 1 h after hyperthermia. The disparity between HO-2 mRNA and protein distribution clearly indicates cell-specific differences in the translational efficiency of HO-2 transcripts. It appears that HO-2 mRNA translation is linked to the maturation and expression of a factor(s) that regulates this process. This, in turn, appears to coincide with sperm development. HO-1 activity, on the other hand, which has a transcriptional component to its regulation, may have a role in maintenance of the conditions required for spermatogenesis.
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PMID:Distribution of constitutive (HO-2) and heat-inducible (HO-1) heme oxygenase isozymes in rat testes: HO-2 displays stage-specific expression in germ cells. 772 Jun 78

Evidence that carbon monoxide can serve as an intercellular messenger in brain, a role much like that demonstrated for nitric oxide in various tissue, prompted us to investigate whether carbon monoxide participates in long-term potentiation (LTP), the cellular mechanism that may underlie certain forms of learning and memory. Although LTP is triggered in the postsynaptic neuron, at least some fraction of LTP is expressed presynaptically as an increase in the quantity of neurotransmitter released. Thus, a retrograde signal must form the communication link between the postsynaptic site of induction and the presynaptic site of expression. To test whether carbon monoxide might act as a retrograde signal in LTP, we have investigated the effect on LTP of inhibitors of the enzyme haem oxygenase-2, which catalyses the production of carbon monoxide in the brain. We find that these inhibitors prevent the induction of LTP and have no effect on one form of long-term depression. Furthermore, they will reverse LTP that is already established.
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PMID:Reversal of long-term potentiation by inhibitors of haem oxygenase. 832 Dec 80


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