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 hereditary hepatic porphyrias, PV, AIP and HC, are characterized biochemically by increased excretion of porphyrins and the porphyrin precursors ALA and PBG. They are characterized clinically by episodes of acute neurological involvement. The increased production of porphyrins and porphyrin precursors has been shown to be due to partial enzyme blocks along the heme biosynthetic pathway which results in secondary depression of the key enzyme ALA-synthetase. The neurological manifestations could therefore be related to either a decrease in essential heme-proteins or other heme-containing compounds within the nervous system, or to a toxic effect of the over-production of the porphyrin precursors ALA and PBG. There is evidence for and against both theories. Recent work from a number of research groups has shown the porphyrin precursors to have potent pharmacological effects on the nervous system, and these are possibly related to the GABA receptor and binding site-porphyrin precursor interactions. Current studies on therapy of the acute attack have concentrated on suppression of ALA-synthetase activity, and consequently, on reduced ALA and PBG production. A number of such methods of therapy have met with remarkable success and hold promise for the future treatment of the acute attack.
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PMID:The neurological manifestations of porphyria: a review. 32 53

In a group of ten male adults admitted to hospital with clinical symptoms of lead exposure, phenazone, elimination rates, blood delta-amino-laevulinic acid dehydratase (ALA.D) activity, blood lead levels and haemoglobin were measured. Investigations were carried out before, immediately after and again at least 12 weeks after cessation of CaEDTA (sodium calcium edetate) chelation therapy. Following chelation, phenazone elimination rates were increased as assessed by a decrease in half life and increase in clearance. This was significant, both immediately after and 12 weeks after cessation of chelation therapy. The change in rate of phenazone metabolism was associated with improved clinical status, with lowered blood lead levels and raised haemoglobin and ALA.D activity. The results of the study suggest that the depression in phenazone elimination in lead intoxication is possibly due to depressed hepatic cytochrome P450 levels.
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PMID:The effects of industrial lead poisoning on cytochrome P450 mediated phenazone (antipyrine) hydroxylation. 41 77

1. A therapeutic trial of intravenous hematin is presented. Eleven cases of AIP and one of VP who did not improve with conventional treatment (high carbohydrate intake) received this new agent. 2. Urinary ALA, PBG and, when possible, uroporphyrin and coproporphyrin were used to monitor the chemical response to the treatment. Objective clinical parameters of hypertension and tachycardia were followed when present in addition to subjective estimates of acute porphyric symptomatology (abdominal pain, backache, extremity pain and paresthesias, weakness, depression, etc.). 3. At a dosage of approximately 3 mg/kg, diminution of urinary ALA and PBG excretion was achieved in every patients. Hypertension and tachycardia improved in those instances where they were observed in association with the attack. Also, subjective improvements in the clinical status of the patients were observed frequently. 4. Hematin appears to be a promising therapeutic agent for the treatment of acute attack forms of porphyria.
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PMID:Hematin therapy for acute porphyria. 44 61

Pregnant and nonpregnant rats were exposed for 21 days to an aerosol containing 1, 3 and 10 mg lead/m3 air and to a combination of 3 mg Pb/m3 and 500 ppm carbon monoxide (CO). Pregnant and nonpregnant rats exposed to uncontaminated air served as controls. The activity of the fetal delta-aminolevulinic acid dehydratase (ALA-D) was less inhibited by lead than the maternal activity. Furthermore, the degree of inhibition was highly reduced in the fetuses by additional CO-inhalation, whereas in adult animals the depression of the ALA-D was accentuated by additional CO-inhalation in accordance with epidemiological data. Therefore, it is concluded that the mode of plumbic inhibition of the ALA-D activity differs in fetuses from that in adults. Furthermore, the adaptation to the inhibition of the ALA-D by de novo synthesis of this enzyme was less in fetuses than in adult rats. The high lead aerosol concentration reduced hematocrit and body weight of the fetuses, but it did not influence these parameters in adult rats, thus pointing to a higher lead-sensitivity of the fetal than the adult organism. A stronger inhibition of maternal ALA-D activity than of the activity of nonpregnant animals possibly indicates a higher susceptibility to lead in pregnancy.
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PMID:Effects of lead inhalation exposures alone and in combination with carbon monoxide in nonpregnant and pregnant rats and fetuses. II. Effects on delta-aminolevulinic acid dehydratase activity, hematocrit and body weight. 60 24

We studied the effects of azidothymidine (AZT) on rat bone marrow heme metabolism and colony growth as determined by assays of granulocyte-macrophage (CFU-GM), erythroid (CFU-E), burst-forming erythroid (BFU-E), and alpha-aminolevulinic acid synthase (ALAS), the first enzyme in the heme pathway. In all cases, AZT (1-0.01 microM) was found to be toxic to bone marrow colony growth. When AZT was included in colony assays, 1 microM resulted in 98-100% inhibition, whereas lower concentrations (0.01 microM) inhibited growth by 58-76%. In addition, cultures from AZT-treated animals had a marked reduction in colony growth as compared with sham controls. In most cases, hemin (10(-5) M) was found to overcome some of the colony inhibitory effects of AZT. Analysis of heme metabolism indicated that ALAS activity was reduced by 71% in bone marrow cells from treated animals. ALAS activity for control was 204 +/- 33 pM ALA formed/4 X 10(6) cells/hr, whereas ALAS activity from AZT-treated animals was only 60 +/- 3 pM ALA formed/4 x 10(6) cells/hr. It is considered that AZT toxicity may be due to a depression in the pool of available heme, which is required for adequate hematopoiesis.
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PMID:Role of heme metabolism in AZT-induced bone marrow toxicity. 238 64

Previous studies on alpha-lactalbumin induced fusion of phosphatidylserine/phosphatidylethanolamine vesicles are extended to vesicles composed of various combinations of phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine and cardiolipin. It was found that inclusion of phosphatidylcholine in the vesicles results in a depression of fusion. This depression of fusion appears to be caused by a reduction in the amount of irreversibly bound alpha-lactalbumin to vesicles containing phosphatidylcholine. It is suggested that in this system fusion is dependent upon the extent by which a particular protein segment penetrates the bilayer.
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PMID:Effect of phosphatidylcholine on the alpha-lactalbumin-induced fusion of vesicles. 281 8

Some parameters of haem synthesis were estimated in 60 uraemic patients (30 non-dialysed, 30 dialysed) and in 30 matched controls. Serum delta-aminolaevulinic acid and erythrocyte coproporphyrin and protoprophyrin were found significantly higher in the non-dialysed uraemics than in the controls. Erythrocyte delta-aminolaevulinic acid dehydrase (ALA-D) activity was 498 +/- 174 mumol/h.l in the non-dialysed patients, 321 +/- 146 in the dialysed (just before haemodialysis) and 833 +/- 281 in the healthy controls, the differences between these groups all being statistically significant (p less than 0.001). After haemodialysis the enzymic activity in the dialysed group increased significantly (380 +/- 167, p less than 0.001), but remained lower than normal (p less than 0.001). A similar pattern - although with less statistical significance of the differences between groups - was observed concerning erythrocyte uroporphyrinogen I synthase activity. Incubation of normal erythrocytes with uraemic plasma resulted in a considerable decrease of their ALA-D activity (from 830 +/- 263 to 616 +/- 126) while incubation of uraemic erythrocytes with normal plasma increased their ALA-D (from 384 +/- 139 to 494 +/- 77). Addition of zinc in the haemolysate caused a similar induction of ALA-D in both controls and uraemics. The zinc-induced uraemic ALA-D practically reached normal levels. The mechanism of enzymic depression and the possible role of elevated delta-aminolaevulinic acid concentrations (to which depressed ALA-D activity considerably contributes) in the pathogenesis of the neurologic manifestations of uraemia, are discussed.
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PMID:Some parameters of haem synthesis in dialysed and non-dialysed uraemic patients. 285 53

delta-Aminolevulinate dehydratase (ALA-D:porphobilinogen synthase, 5-aminolevulinate hydro-lyase, EC 4.2.1.24) activity was depressed markedly in red cells of rats exposed to 0.21 g/m3 styrene, a chemical widely used in commercial products. The depression was not restored in vitro after treatment with dithiothreitol and zinc. Consistent with this finding, radioimmunoassay of the enzyme protein demonstrated reduction in the enzyme concentration by styrene exposure. There was a good correlation between the decrease in enzyme activity and its concentration in the styrene-treated animals, suggesting that the depression of the enzyme activity was essentially due to the reduction in the enzyme content. Decrease in the enzyme content in bone marrow cells to almost the same extent as that in erythrocytes seems to indicate the decreased synthesis of ALA-D in the bone marrow. In vitro studies showed that styrene 7,8-oxide, the major intermediate of styrene metabolism, decreased the activity of purified ALA-D but that styrene, the parent compound itself, had no inhibitory effect. The activity and concentration of erythrocyte ALA-D in workers chronically exposed to styrene were also depressed significantly. These findings indicate that the styrene exposure-mediated decrease of ALA-D activity in erythrocytes was a reflection of reduction in the enzyme protein, which may have been the result of styrene 7,8-oxide action, and they suggest that a similar process may also be involved in the reduction of erythrocyte ALA-D in styrene-exposed workers.
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PMID:Decreased erythrocyte delta-aminolevulinate dehydratase activity after styrene exposure. 382 52

Two new lines of rats have been selectively bred for high or low active avoidance responding--the Australian High (AHA) and Low (ALA) Avoiders. Ethanol (1-1.5 g/kg body weight, i.p.) improved acquisition of active avoidance responding only in ALA, whereas alpha-methyl-p-tyrosine (AMPT; 80 mg/kg body weight, i.p.) seemed to selectively impair acquisition of responding in AHA. The combination of ethanol and AMPT caused a general depression of behaviour. The 2 lines did not differ consistently in the latency to escape from shock, locomotor activity, 'emotionality' or passive avoidance responding. Ethanol had no effect on locomotor activity or 'emotionality', but increased the latency to escape from shock and impaired passive avoidance responding in both lines.
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PMID:The Australian High and Low avoidance rat strains: differential effects of ethanol and alpha-methyl-p-tyrosine. 687 Oct 17

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


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