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 trace metals nickel and platinum, which are not substrates for ferrochelatase and thus do not form heme in biological systems, were found to act similaryl to cobalt, and heme itself, in regulating heme metabolism in liver and kidney. These metals induced heme oxygenase activity in both organs with the peak of induced enzyme activity reached approximately 16 hr after single injections in rats. Both metals caused transient depression of cellular glutathione content followed by increases above normal after 12 hr in liver. Nickel and platinum were more potent inducers of heme oxygenase in kidney than in liver (10-13 times normal versus 5-6 times normal). At high concentrations, they inhibited heme oxygenase [heme, hydrogen-donor:oxygen oxidoreductase (alpha-methene-oxidizing, hydroxylating), EC 1.14.99.3] in vitro. Both were active in regulating heme metabolism only when administered in the ionic form. Complexing of the metals with sulfhydryl agents completely blocked their actions on heme metabolism. Administration of cysteine orally prior to or shortly after administration of the metals had a similar blocking effect. Nickel and platinum produced depression of delta-aminolevulinate synthase [succinyl-CoA:glycine c-succinyltransferase (decarboxylating), EC 2.3.1.37] activity in liver, but neigther inhibited this rate-limiting ennzyme for heme synthesis in vitro. Furthermore, despite the substantial decreases in cellular heme and hemoprotein contents mediated by the metal, production of delta-amimolevulinate synthase did not undergo the compensatory increase that would be expected if there were a direct reciprocal feedback relationship between cellular heme level and synthesis of this enzyme. These findings indicate that it is not necessary for metal ions to be chelated in the porphyrin ring in order to regulate the enzymes of heme synthesis and heme oxidation. Accordingly, it is suggested that the iron atom of heme is the proximately active regulator of delta-aminolevulinate synthase and heme oxygenase--actions generally ascribed to the iron-tetrapyrrole complex itself--and that the tetrapyrrole moiety of the complex functions primarily as a means of transport of the metal to regulatory sites in cells.
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PMID:Regulation of heme pathway enzymes and cellular glutathione content by metals that do not chelate with tetrapyrroles: blockade of metal effects by thiols. 26 10

1 Pretreatment of rats with intraperitoneal injections of lead was shown to result in a depression of the microsomal mixed function oxidase system, as assessed by a decrease in hepatic microsomal P-450 and b5 content and by a decrease in the activity of the enzymes aniline hydroxylase and aminopyrine demethylase. Lead had a more marked effect on cytochrome P-450 than b5. 2 The activity of the rate-limiting enzyme of haem biosynthesis, delta-aminolaevulinic acid synthase, was inversely correlated with the microsomal cytochrome P-450 content. 3 The activity of the haem biosynthetic enzymes delta-aminolaevulinic acid dehydratase, coproporphyrinogen oxidase and ferrochelatase were decreased by increasing lead pretreatment. 4 The activity of the haem catabolic enzyme, haem oxygenase, was increased by lead pretreatment.
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PMID:Hepatic drug metabolism and haem biosynthesis in lead-poisoned rats. 65 97

In these studies the effects of ingested arsenic (As(+5)) on hepatic heme biosynthetic capability and hemoprotein function in adult male rats were investigated. Animals exposed for 6 weeks to 0, 20, 40, or 85 ppm sodium arsenate in the drinking water suffered depression of hepatic delta-aminolevulinic acid (ALA) synthetase and heme synthetase (ferrochelatase) activities, with maximal decreases to 67 and 55% of control levels, respectively, at 85 ppm. Concomitantly, urinary uroporphyrin levels were elevated by as much as 12 times, and coproporphyrin by as much as 9 times, control values. The rate of incorporation of (3)H-ALA into mitochondrial and microsomal hemes was depressed by 40-50% at 20 ppm but was increased with regard to controls by as much as 150% at the higher treatment levels. A similar biphasic pattern was observed in regard to (14)C-leucine incorporation into cellular membranal proteins. In contrast, the levels of ALA dehydratase, uroporphyrinogen I synthetase, aminopyrine demethylase, and cytochrome P-450 were not significantly changed in As(+5)-treated rats. These results support the hypothesis that chronic, low level, arsenic exposure results in selective inhibition of mitochondrial-bound heme biosynthetic pathway enzymes (ALA synthetase and heme synthetase) resulting in a substantial increase in urinary porphyrins, uniquely characterized by a greater increase in uroporphyrin than coproporphyrin levels. These changes occur independent of, or prior to, alterations in hepatic hemoprotein-dependent functions and may thus serve in the clinical analysis of pretoxic exposure to arsenic compounds in human populations.
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PMID:Effects of chronic arsenic exposure on hematopoietic function in adult mammalian liver. 90

1. The activities of six of the enzymes of haem biosynthesis have been assayed in peripheral blood from patients with lead poisoning, acute intermittent porphyria or hereditary coproprophyria. 2. Compared with normal subjects the lead-poisoned subjects had highly significant depression of delta-aminolaevulinate dehydratase, coproporphyrinogen oxidase and ferrochelatase. 3. Lead-poisoned subjects had highly significant elevation of delta-aminolaevulinate synthase activity. 4. delta-Aminolaevulinate synthase activity was inversely related to the haemoglobin concentration. 5. Increased delta-aminolaevulinate synthase and decreased delta-aminolaevulinate dehydratase activity are also found in acute intermittent porphyria. 6. Increased delta-aminolaevulinate synthase, normal prophobilinogen deaminase and uroporphyrinogen decarboxylase and decreased coproporphyrinogen oxidase are found in both lead poisoning and hereditary coproporphyria. 7. These enzyme changes explain the recognized patterns of porphyrins and prophyrin precurosrs in blood and urine in these conditions.
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PMID:Alterations in the activity of enzymes of haem biosynthesis in lead poisoning and acute hepatic prophyria. 91 57

The toxic side-effects of the immunosuppressive drug cyclosporin (CsA) include testicular dysfunction and a decline in circulating testosterone. However, mechanisms for the consistently observed CsA-mediated depression of serum testosterone levels are unclear because of conflicting reports concerning circulating gonadotropin levels and incomplete studies of intratesticular steroidogenesis. To elucidate these mechanisms, endocrine-regulated testicular steroidogenesis and heme metabolic parameters were studied in male rats given sc injections of either 25 or 40 mg/kg.day CsA for 6 days and then killed on the seventh day. Consistent with earlier reports, CsA treatment dramatically suppressed serum testosterone levels (less than 20% of control at both CsA doses). Additionally, the intratesticular testosterone content declined with the higher CsA dose. Serum LH and FSH levels were elevated up to 2- to 4-fold after the higher CsA treatment regimen. Measurement of decreases in testicular receptors for LH revealed for the first time that CsA treatment significantly reduced the ability of the testes to respond to normal or elevated circulating levels of LH. In animals receiving higher dose of the drug, cytochrome P-450-dependent mitochondrial cholesterol side-chain cleavage activity, which is the rate-limiting step in steroidogenesis, was markedly reduced to a mere 30% of the control value. Additionally, the activity of the microsomal cytochrome P-450-dependent 17 alpha-hydroxylase was decreased to less than half of the control value. Biotransformation of the prototype drug, benzo(a)pyrene, as well as microsomal cytochrome P450 levels declined significantly after the higher CsA dose, suggesting that CsA has an adverse affect on testicular cytochromes P-450 in general. In addition, CsA treatment altered heme metabolic parameters; significant increases in the activity of uroporphyrinogen-I synthetase and total porphyrin content were noted. Conversely, the activity of ferrochelatase, the enzyme that incorporates iron into porphyrin to form heme molecule, decreased significantly, as did the total heme levels. The latter was reduced to only 61% of control values. The findings suggest the likelihood that the observed inhibition of heme formation may contribute substantially to the reduced levels of microsomal cytochromes P-450 and steroidogenic activities that depend on them. Taken collectively, these data suggest a plausible mechanism by which CsA may induce testicular dysfunction; as the result of a combination of reduction in the number of LH receptors and a suppression of heme formation, the hemoprotein-dependent steroidogenic enzymes activities are compromised, leading to an impairment of normal testicular function.
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PMID:Cyclosporin-mediated depression of luteinizing hormone receptors and heme biosynthesis in rat testes: a possible mechanism for decrease in serum testosterone. 193 94

Administration in the drinking water of the orally-active iron chelator 1,2-diethyl-3-hydroxypyridin-4-one (CP94) to C57BL/10ScSn mice caused the development of hepatic protoporphyria. This was detected after 1 week and continued as long as the chelator was given (15 weeks). The more hydrophilic 1,2-dimethyl- and 1-hydroxyethyl,2-ethyl-analogues (CP20 and CP102) were also tested, but they were both inactive in inducing accumulation of protoporphyrin in the liver. Restriction of in vivo iron supply for ferrochelatase seemed a likely mode of action, but an approximately 30% decrease in activity of this enzyme was also observed when measured in vitro. Extracts of livers from mice given CP20, CP94, and CP102 showed no potential to inhibit mouse ferrochelatase, in contrast to the findings with an extract from mice treated with the known porphyrogenic chemical 4-ethyl-3, 5-diethoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine, indicating that ferrochelatase inhibition did not occur by the formation of an N-ethyl-protoporphyrin derived from metabolism by cytochrome P450, CP20, CP94, CP102, and CP117 (the pivoyl ester of CP102) all caused significant depression of the levels of ferritin-iron and total nonheme iron, but only CP94 caused the significant accumulation of protoporphyrin. Protoporphyria did not occur with iron overloaded C57BL/10ScSn mice or in SWR mice that had elevated basal iron status. Although the protoporphyrin had only a small effect on the total levels of the hemoprotein cytochrome P450 in C57BL/10ScSn mice, the activity of the CYP2B isoforms of cytochrome P450 was actually induced in both strains. The results show that CP94 could cause protoporphyria in individuals of low iron status, perhaps through specifically targeting particular iron pools available to ferrochelatase and by concomitantly stimulating heme synthesis.
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PMID:Protoporphyria induced by the orally active iron chelator 1,2-diethyl-3-hydroxypyridin-4-one in C57BL/10ScSn mice. 902 37

The bioaccumulations of lead in the liver and hepatic microsomes of fish after 1, 3, 7, 14, 28, and 45 days exposure were studied. In addition, the relationship between the bioaccumulated lead in both hepatic microsomes and the liver and their haem biosynthetic enzymes were studied. Lead toxicity was shown to result in a depression of the microsomal mixed function oxidase system, as assessed by a decrease in hepatic microsomal cytochrome P-450 and b5 content and by a decrease in the activity of the enzymes aniline hydroxylase and aminopyrine demethylase. Lead had a more marked effect on cytochrome P-450 than b5. The activity of the rate-limiting enzyme of haem biosynthesis, delta-aminolevulinic acid synthase, was inversely correlated with the microsomal cytochrome P-450 content. The activity of the heam biosynthetic enzymes delta-aminolevulinic acid dehydratase, coproporphyrinogen oxidase and ferrochelatase were decreased by increasing lead pretreatment. The activity of the haem catabolic enzyme, haem oxygenase, was increased by concentration and length of time to lead exposure.
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PMID:The effect of lead bioaccumulation on haem biosynthetic enzymes in fish. 1525 3