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)

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

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) (233 nmol/kg) causes a significant increase of hepatic uroporphyrin, heptacarboxyporphyrin, and total porphyrins in female C57BL/6 mice, ovariectomized C57BL/6 mice, male C57BL/10 mice, and male C57BL/6 mice 3 weeks after treatment. In contrast, 6-methyl-1,3,8-trichlorodibenzofuran (MCDF) was inactive at a dose of 750 mumol/kg. Cotreatment of the mice with TCDD (233 mol/kg) plus MCDF (750 mumol/kg) resulted in partial antagonism of TCDD-induced hepatic porphyrin accumulation only in the female mice. Parallel studies in female C57BL/6 mice showed that the TCDD-induced porphyria was accompanied by the induction of hepatic microsomal aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) activities and the depression of uroporphyrinogen decarboxylase (UROD). MCDF (750 mumol/kg) did not significantly affect these enzymes. In the cotreatment studies (MCDF plus TCDD), MCDF partially antagonized TCDD-induced hepatic porphyrin accumulation but did not affect the levels of hepatic AHH, EROD, or UROD. These results indicate that other factors, in addition to the induction of cytochrome P450-dependent monooxygenases and depressed UROD activity, are important in TCDD-induced porphyria in C57BL/6 female mice.
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PMID:2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced porphyria in genetically inbred mice: partial antagonism and mechanistic studies. 278 54

The potentials of octachlorostyrene (OCS) and hexachlorobenzene (HCB) to induce liver microsomal ethoxyphenoxazone deethylation (an indicator of induction of 3-methylcholanthrene and beta-naphthoflavone-like cytochrome P-450 monoxygenase activity) and cause porphyria in male C57BL/6 and C57BL/10 mice and female F344 rats were compared. Ethoxyphenoxazone deethylation was induced much more by HCB than by OCS in both of these strains of mice (although neither OCS nor HCB greatly induced deethylation in the DBA/2 strain). In rats ethoxyphenoxazone deethylase was induced 26-fold by HCB but only four-fold by OCS, whereas dealkylation of pentoxyphenoxazone (an indicator of phenobarbital-like induction) increased 43- and 36-fold, respectively. Both chemicals were poor inducers of dealkylation of pentoxyphenoxazone in mice. When fed HCB continuously but not when given OCS, C57BL/6 and C57BL/10 mice (both after pretreatment with iron) and F344 rats developed porphyria with a depression of hepatic uroporphyrinogen decarboxylase activity. The results illustrate that in these species OCS and HCB cannot be considered as equally efficient agents for inducing ethoxyphenoxazone deethylation or causing porphyria. If these effects are mediated through binding to the aromatic hydrocarbon responsiveness (Ah) receptor, HCB would appear to have a much greater affinity than OCS despite the face that neither chemical possesses a structure currently considered to be necessary for efficient binding.
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PMID:Distinction between octachlorostyrene and hexachlorobenzene in their potentials to induce ethoxyphenoxazone deethylase and cause porphyria in rats and mice. 327 68

An inhibitor of hepatic uroporphyrinogen decarboxylase (EC 4.1.1.37) was demonstrated in heat-treated extracts of livers from C57BL/10ScSn mice with iron overload after a single dose (100 mg/kg; 350 mumol/kg) of hexachlorobenzene (HCB). Inhibition was not due to accumulated uroporphyrin since this could be removed by a SEP-PAK C18 cartridge without affecting inhibitor activity. The presence of the inhibitor could be first demonstrated 2 weeks after mice received HCB and before major elevation of hepatic porphyrin levels. Maximum inhibitory potential was reached at about 8 weeks and was still detected 25 weeks after the chemical, thus paralleling the depression of enzyme activity reported previously [Smith, Francis, Kay, Greig & Stewart (1986) Biochem. J. 238, 871-878]. The inhibitor was not detected following treatment of mice with either iron or HCB alone or after the decarboxylase activity was destroyed in vitro by the combination of uroporphyrin and light. The formation of the inhibitor by inbred mouse strains nominally Ah-responsive (C57BL/6J, C57BL/10ScSn, BALB/c, C3H/HeJ, CBA/J and A/J) and Ah-nonresponsive (SWR, AKR, 129, SJL, LP and DBA/2) did not correlate fully with their reported Ah-phenotype. There was a correlation amongst the Ah-responsive strains only, with hepatic ethoxyphenoxazone de-ethylase activity induced in parallel experiments by treatment with beta-naphthoflavone. De-ethylase activity induced by HCB, however, was considerably less than that with beta-naphthoflavone, which has not been reported as porphyrogenic. Other polyhalogenated chemicals, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,4,2',3',4'-hexachlorobiphenyl and hexabromobenzene, also caused the formation of the inhibitor of uroporphyrinogen decarboxylase.
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PMID:Chemically-induced formation of an inhibitor of hepatic uroporphyrinogen decarboxylase in inbred mice with iron overload. 367 56

Hexachlorobenzene (HCB) was fed to male and female F344 rats as 0.02% of the diet for 15 weeks. Females developed a massive porphyria, due to depression of uroporphyrinogen decarboxylase activity, whereas males did not. Although hepatic non-haem iron levels in control females were 3-5 times greater than males (iron is implicated in the pathogenesis of this condition) preloading the latter with iron did not increase their susceptibility. After 90 weeks of HCB treatment 100% of surviving females had multiple liver tumours which were strongly gamma-glutamyl transpeptidase (GGT) positive and histologically classified as neoplastic nodules or hepatocellular carcinomas. In contrast, only 16% of males developed tumours which were smaller and fewer in number per liver than those in females. Accumulation of porphyrins was still significantly less in males than females although no uroporphyrinogen decarboxylase activity was detected in treated livers of either sex. No differences in porphyrin levels or enzyme activity were found between tumours and surrounding tissue showing that tumours did not revert to a non-porphyric state. The sex difference in tumour response could not be explained by differences in hepatic HCB concentrations. Non-haem iron concentrations of livers fell after HCB treatment for 90 weeks in both sexes and were even lower in tumours. These studies demonstrate that not only are female rats far more sensitive than males to the porphyrinogenic effects of HCB but also to the hepatocarcinogenic actions, suggesting a link between these two manifestations of toxicity that may also apply to other polyhalogenated aromatics.
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PMID:Hepatocarcinogenicity of hexachlorobenzene in rats and the sex difference in hepatic iron status and development of porphyria. 398 65

Hepatic uroporphyrinogen decarboxylase activity in male C57BL/10 mice was maintained in regenerated liver after recovery from two-thirds hepatectomy. In contrast, there was little increase in enzyme activity in regenerated liver from animals previously treated with hexachlorobenzene (HCB) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). These chemicals initially cause depression of uroporphyrinogen decarboxylase activity over a time much longer than the period allowed for regeneration. Estimation of HCB levels showed that there was only a small amount of redistribution to the liver during regrowth. The results demonstrate that HCB and TCDD induce either formation of a toxic metabolite or some other inhibitory process and that this can be sustained for a long period which delays recovery to the normal state.
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PMID:Continued depression of hepatic uroporphyrinogen decarboxylase activity caused by hexachlorobenzene or 2,3,7,8-tetrachlorodibenzo-p-dioxin despite regeneration after partial hepatectomy. 400 97

Virgin female Agus rats were fed a diet containing hexahalogenated benzenes (700 nmol/g of food) for 70 days. The liver concentrations of these compounds were then determined and correlated with any depression in uroporphyrinogen decarboxylase activity and increases in porphyrin levels (indicating the induction of porphyria). Hepatic concentrations of the compounds corresponded to the series F greater than Cl greater than Br. However, depression of decarboxylase activity and increase in porphyrin levels were Cl greater than Br greater than F, (hexachlorobenzene and hexabromobenzene increased porphyrins by 513- and 17-fold respectively) suggesting that at its site of action in the liver hexabromobenzene may be more porphyrogenic than the chlorine analogue. This may suggest a relationship between the strength of the carbon-halogen bond and the induction of porphyria.
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PMID:Relative abilities on a molar basis of hexafluoro-, hexachloro- and hexabromobenzenes to decrease liver uroporphyrinogen decarboxylase activity and cause porphyria in female rats. 739 29

In mice, depression of hepatic uroporphyrinogen decarboxylase (UROD) leading to porphyrin accumulation (uroporphyria) occurs with chlorinated ligands of the aryl hydrocarbon (AH) receptor especially after iron overload. However, in the absence of chlorinated ligands, iron itself will eventually cause uroporphyria, but this response is not associated with the Ahr genotype. These effects are potentiated by administration of the haem precursor 5-aminolaevulinate (ALA). The aim of this study was to investigate the effects of ALA alone. Prolonged administration of 2 mg ALA/mL in the drinking water to SWR mice also led to decarboxylase insufficiency (11% of control) and uroporphyria by 8 weeks, whereas DBA/2 mice did not show reduced enzyme activity. Both strains are considered AH nonresponsive and analysis of the Ahr gene using restriction fragment length polymorphism was consistent with SWR, like DBA/2, possessing the Ahrd allele. Exposure of isolated hepatocytes to ALA (150-500 microM) for up to 48 hr showed a significant accumulation of both uroporphyrin and coproporphyrin in the medium, which for uroporphyrin particularly was significantly greater with SWR than with DBA/2 cells. Basal in vivo CYP1A2 activity, measured as microsomal methoxyresorufin dealkylation, was significantly greater in SWR than in DBA/2 mice (1.3-fold), but it was unclear whether this was sufficient to explain the marked difference in sensitivities of the two strains. Despite SWR mice being AH nonresponsive, uroporphyria and decarboxylase depression after an initial iron overload and ALA for 3 weeks were greatly potentiated by a single dose (100 mg/kg) of hexachlorobenzene (a weak AH ligand). The results demonstrate that there is a genetic difference in mice independent of the Ahr genotype and response to iron, which influences the susceptibility to ALA-induced uroporphyria. Thus chemicals, iron and ALA can act independently, but also together, to cause porphyria in susceptible individuals.
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PMID:Uroporphyria induced by 5-aminolaevulinic acid alone in Ahrd SWR mice. 893 51

An experimental model of porphyria cutanea tarda, consisting of depressed hepatic uroporphyrinogen decarboxylase (URO-D) activity and accumulation of highly carboxylated porphyrins in the liver, was produced in 3 weeks in Fischer 344 rats. A single administration of a polychlorinated biphenyl mixture (Aroclor 1254) to iron-loaded female rats maintained continuously on delta-aminolevulinic acid supplemented drinking water produced the porphyric state. Without iron loading, URO-D activity appeared slightly less inhibited (33% of normal vs 23% of normal) but porphyrin accumulation was dramatically less (70 vs 605 micrograms porphyrin/g liver). Similar treatment in male rats produced URO-D activities of 54 and 70% of normal with and without iron loading, respectively, and porphyrin concentrations of 76 and 17 micrograms/g. When hexachlorobenzene was substituted for Aroclor 1254 treatment in female rats, URO-D activity was 61 and 69% of normal (with and without iron loading, respectively) and liver porphyrin concentrations were 96 and 25 micrograms/g, respectively. Hexachlorobenzene did not produce significant porphyric effects in male rats. Aroclor 1254 induced CYP1A to a greater extent in females than in males and to a greater extent than hexachlorobenzene, which showed a greater propensity to induce CYP2B. Overall correlation between URO-D activity depression and porphyrin accumulation was highest when fitted to an exponential curve, indicating the importance of the extreme of the depression URO-D activity in evoking experimental porphyria cutanea tarda.
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PMID:Cytochrome P450 induction, uroporphyrinogen decarboxylase depression, porphyrin accumulation and excretion, and gender influence in a 3-week rat model of porphyria cutanea tarda. 943 24

Many toxicological disorders, in common with numerous human diseases, are probably the consequence of multigene interactions with a variety of chemical and physiological factors. The importance of genetic factors may not be obvious initially from association studies because of their complexity and variable penetrance. The human disease, porphyria cutanea tarda (PCT), is a skin disease caused by the photosensitizing action of porphyrins arising secondary to the decreased activity of an enzyme of heme biosynthesis, uroporphyrinogen decarboxylase (UROD), in the liver. It is triggered by idiosyncratic hepatic interaction between genetic factors and chemicals such as alcohol, estrogenic drugs, and polyhalogenated aromatics. PCT and its animal models are known collectively as the hepatic uroporphyrias. There is strong evidence for the participation of iron in the pathogenesis of these conditions. Mouse models have been used to explore the relative importance of a variety of agents such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), alcohol, and iron in the development of uroporphyria and to elucidate the mechanism of the depression of hepatic UROD activity. Mutations of the UROD and hemochromatosis (HFE) genes are genetic factors in some PCT patients which can be mimicked in mice heterozygous for the Hfe and Urod null genes. Association studies of uroporphyria induced by TCDD or hexachlorobenzene with DNA markers in mouse intercrosses have shown the participation of other, unknown, genetic factors in addition to the strong influence of the Ahr gene. The pathogenesis of hepatic uroporphyrias exemplifies the complexity of the interactions between chemical and genetic factors that can contribute to the hepatotoxicity of chemicals.
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PMID:Complex gene-chemical interactions: hepatic uroporphyria as a paradigm. 2009 33


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