Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.14.99.3 (heme oxygenase)
 4,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

After a single dose of cobaltous chloride there was a marked inhibition of liver 5-aminolaevulinate (5-ALA) synthetase (at 1 h) and this was followed in turn by a stimulation of haem oxygenase (at 3 h) and by a return of the synthetase activity to normal or above normal (at 17 h). Bile cannulation experiments were performed 1 and 17 h after administration of CoCl2. At 1 h there was a marked decrease in bile porphyrin content, no change in bile concentration of bilirubin, but a decrease in the conversion of [14C]-5-ALA to bilirubin and to liver haem. At 17 h, an the other hand, the bile excretion of both porphyrins and bilirubin was significantly greater than in controls and more radioactivity (from [14C]-5-ALA) appeared in the bile as bilirubin. It is concluded that the effects of cobalt on liver haem metabolism are complex and time-dependent. There is first inhibition of liver haem synthesis at two different steps of the pathway (synthesis of 5-ALA and conversion of 5-ALA to haem), with diversion of [14C]-5-ALA into a relatively stable liver pool different from haem; and at a later stage there is also an increase in the rate of liver haem degradation.
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PMID:The effect of cobaltous chloride on liver haem metabolism in the rat. Evidence for inhibition of haem synthesis and for increased haem degradation. 100 89

1. Heme synthesis from delta-aminolevulinic acid (delta-ALA) in freshly isolated rat hepatocytes was maximal at 100 microM with a rate of approx. 7 nmol being synthesized per g wet weight cells. 2. Approximately 8% of synthesized heme was converted to bilirubin and 50% of the newly synthesized bilirubin was conjugated. 3. The ratio of di to monoconjugate was approx. 2.5. Incorporation of delta-ALA into bilirubin was increased by additional delta-ALA, heme and was also doubled in cells isolated from animals treated with CoCl2. 4. Bilirubin formation was inhibited approx. 90% by in vitro treatment with heme oxygenase inhibitors zinc and tin protoporphyrin.
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PMID:Bilirubin production and conjugation from newly formed heme in isolated rat hepatocytes. 142 22

Heme oxygenase has been considered to be involved in the predominant pathway of heme degradation in vivo. However, alternative pathways involving cytochrome P-450 reductase, and lipid peroxidation, have previously been demonstrated in vitro, and studies with cultured rat hepatocytes were interpreted to show a majority of endogenous hepatic heme breakdown by non-heme oxygenase pathways. To clarify the pathway of heme breakdown in hepatocytes and the role of heme oxygenase in this process, cultured hepatocytes were pre-labelled with 5-[5-14C]aminolevulinate [( 14C]ALA). Radioactivity in heme, carbon monoxide, and bile pigments was measured for 8-24 h after the removal of [14C]ALA. In cultured chick embryo hepatocytes, which lack biliverdin reductase, the rate of production of biliverdin IXa was closely similar to the rate of catabolism of exogenous heme and radioactivity in carbon monoxide and biliverdin IXa was similar to the loss of radioactivity from endogenous heme. These results support the conclusion that heme breakdown occurred predominantly, if not solely, by heme oxygenase. Also, no evidence of non-heme oxygenase pathways was found in the presence of tin protoporphyrin, an inhibitor of heme oxygenase or mephenytoin, an inducer of both cytochrome P-450 and heme oxygenase. Similarly, in untreated cultured rat hepatocytes, radioactivity in carbon monoxide corresponded with loss of radioactivity in endogenous heme. In other experiments with chick hepatocyte cultures, rates of heme synthesis and breakdown were measured, and data were fitted to various models of hepatic heme metabolism. The results observed were consistent only with models in which an appreciable fraction (control cells, 17%, mephenytoin treated cells, 41%) of the newly synthesized heme was degraded rapidly to biliverdin.
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PMID:Heme catabolism in cultured hepatocytes: evidence that heme oxygenase is the predominant pathway and that a proportion of synthesized heme is converted rapidly to biliverdin. 275 38

Sn (tin)-mesoporphyrin (Sn-protoporphyrin in which the vinyl groups at C2 and C4 have been reduced to ethyl groups) when incubated with rat splenic microsomal heme oxygenase proved to be a potent competitive inhibitor of enzyme activity in vitro, with a Ki of 0.014 microM. Sn-mesoporphyrin (1 mumol/kg body wt) also inhibited hepatic, renal, and splenic heme oxygenase activity in vivo in adult animals for extended periods of time. Sn-mesoporphyrin (1 mumol/kg body wt) prevented the transient increase in serum bilirubin 24 h after birth in the rat neonate and substantially reduced the levels of serum bilirubin in ALA (delta-aminolevulinic acid) induced hyperbilirubinemia in the 7-day-old suckling neonate. Tissue heme oxygenase activity was decreased in both animal models of hyperbilirubinemia. Sn-mesoporphyrin administration led to a prolonged increase in the heme saturation of hepatic tryptophan pyrrolase indicating an increase in the "heme pool" related to tryptophan pyrrolase and the compound also suppressed chemically induced hepatic porphyria. The administration of Sn-mesoporphyrin to bile duct-cannulated rats was followed by a prompt and sustained decrease in bilirubin output in bile. In addition the excretion of heme in bile was enhanced in these animals. These studies indicate that Sn-mesoporphyrin, like Sn-protoporphyrin, decreases serum bilirubin by inhibiting the production of bilirubin in vivo and its mode of action is through a sustained competitive inhibition of heme oxygenase. However, when a direct comparison of Sn-protoporphyrin and Sn-mesoporphyrin was made, these studies clearly established that the reduction of the C2 and C4 vinyl groups of the porphyrin macrocycle to ethyl groups increases the effectiveness of the Sn-mesoporphyrin derivative 10-fold or more as compared with Sn-protoporphyrin in inhibiting heme catabolism in the animal model systems examined. Thus alterations in the side chain substituents as well as of the central metal atom can influence in a significant manner the potency of the resultant synthetic heme analog as an agent capable of inhibiting heme degradation in vivo.
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PMID:Reduction of the C2 and C4 vinyl groups of Sn-protoporphyrin to form Sn-mesoporphyrin markedly enhances the ability of the metalloporphyrin to inhibit in vivo heme catabolism. 359 68

The magnitude and duration of drug action is determined partially by the activity of the drug metabolizing enzyme systems in the liver. The pharmacological effectiveness of many drugs is altered during the aging process. In this study, the regulation of heme metabolism and hemoprotein content was examined in livers of aged female rats. The activities of hexobarbital hydroxylase and aniline hydroxylase, indicators of mono-oxygenase function, were decreased in aged rats by 31% and 24%, respectively, as compared to values in young rats. This was accompanied by a proportional decrease in the level of cytochrome P-450 (26%). Additionally, the activity of delta-aminolevulinic acid synthetase (ALA-S), the rate-limiting enzyme in heme synthesis, and the microsomal concentration of heme were also decreased by 33% and 26%, respectively, in these animals. In contrast, the basal activity of microsomal heme oxygenase (MHO), the rate-limiting enzyme in heme degradation, and the percent heme saturation of tryptophan pyrrolase (TPO), a sensitive indicator of changes in the availability of heme in the "regulatory" heme pool, were increased by (87%) and (31%), respectively, in the aged rats. The serum concentration of bilirubin, an indicator of erythrocyte breakdown and/or liver function was likewise increased in these animals. In view of these findings, we suggest that the high activity of MHO and the low level of ALA-S may be a significant causative factor for the decreased microsomal concentration of heme, cytochrome-P-450 and its dependent monooxygenase activities in senescent female rats.
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PMID:Aberration of heme and hemoprotein in aged female rats. 360 51

Old (24-months) rats have lower activities of hepatic delta-aminolevulinic synthase and the microsomal cytochrome P-450 monooxygenase activities--aminopyrine N-demethylase and aniline hydroxylase--as compared to young (2-months) animals. In contrast, the activity of the heme degradative enzyme, heme oxygenase, is higher in the old rats. Cytochrome P-450 and microsomal heme contents were maintained in the old. When inducibility and inhibition of these enzymes were studied, the old rats responded to the same degree as the young. These results indicate that the ability of the heme synthetic and degradative enzymes to respond to decreasing cellular heme levels is not significantly altered with age. The observations that there is a lower baseline activity of ALA-synthase and good maintenance of microsomal heme and cytochrome P-450 content, in spite of elevated heme oxygenase activity in the old, suggest that, at least in the senescent rat, hepatic heme utilization and degradation are only loosely coupled to heme production. It appears, therefore, that alternate sources of heme for cytochrome P-450 are available in the old animals. Furthermore, it is suggested that the old rat has a baseline change in ALA-synthase, heme oxygenase, and cytochrome P-450 that may be overcome under the appropriate conditions.
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PMID:Effect of age on rat liver heme and drug metabolism. 384 17

A study on hepatic heme metabolism with special emphasis to ALA synthetase, ALA dehydratase and heme oxygenase was carried out in cadmium exposed freshwater fish Channa punctatus to enlighten the mechanism of cadmium induced toxicity. Cadmium exposure (0.5-5.0 mg/1) for 7 days increased the hepatic level of ALA, along with the depletion in heme content, which are characteristic to chemical porphyria. The resultant enhancement in the activities of ALA synthetase and heme oxygenase were further shown to be dose dependent. ALA dehydratase activity on the other hand was enhanced only at higher exposure. Time course studies on the enzyme activities and heme content showed that ALA synthetase started to increase after 24 hrs., reached maximum at 7 days and came back nearly to normal level after 30 days of exposure. Simultaneously maximum depletion in heme level occurred on 7 days of exposure, tending to return to normal on 30 day. In addition, attempt has been made to correlate alterations in heme metabolism due to cadmium with the histopathological manifestations in liver.
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PMID:Alterations in hepatic heme metabolism in fish exposed to sublethal cadmium levels. 398 85

Heme metabolism was examined in developing in vitro erythroid colonies (CFUE) and in bone marrow samples taken directly from four normal donors and four patients with sideroblastic anemia. As previously reported, sideroblastic anemia bone marrow cells grew large numbers of CFUE in methylcellulose culture in the absence or presence of erythropoietin. Maximum activities of delta-aminolevulinic acid synthase (ALAS), ALA dehydratase (ALAD), and 14C-ALA incorporation into heme were achieved in normal marrow CFUE after 8 days of culture, whereas heme oxygenase progressively decreased to low levels of activity during the same period. Assays on nucleated bone marrow cells taken directly from patients revealed that ALAS activity was considerably reduced in idiopathic sideroblastic anemia (IASA) and X-linked sideroblastic anemia (X-SA) bone marrow specimens, whereas the activity increased more than twofold (normal levels) when cells were assayed from 8-day CFUE. In all cases, ALAD activity appeared to be within normal levels. Measurement of heme synthesis revealed that normal levels of 14C-ALA incorporation into heme were achieved in IASA cells but were reduced in X-SA cells. In marked contrast to levels in normal cells, heme oxygenase was found to be significantly elevated (two- to fourfold) in bone marrow cells taken directly from patients with IASA and X-SA. Results from this study demonstrate that IASA and X-SA bone marrow cells have disturbances in ALAS and heme metabolism, and that erythropoiesis (CFUE) can be restored to normal levels when cells are cultured in methylcellulose.
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PMID:Regulation of heme metabolism in normal and sideroblastic bone marrow cells in culture. 398 52

Total bilirubin production and relative rates of early labeling of bilirubin (ELB) were determined in rats during postnatal development. Total production was estimated by measuring endogenous rate of excretion of carbon monoxide (VeCO), while ELB was determined by measuring the incorporation of glycine-2-14C and delta-aminolevulinic acid-5-14C(delta-ALA-5-14C) into expired 14CO over a 30-h period after isotope injection. VeCO was considerably higher in 1- and 4-day-old rat pups than in adults, but fell rapidly toward adult values by 9 days of age. 14CO excretion from both isotopic precursors of bilirubin was significantly greater in suckling animals than in postweanling and young adult animals when expressed as a percent of the administered radioactivity. The activity of hepatic heme oxygenase showed a similar pattern of postnatal change to 14CO excretion from both glycine-2-14C and delta-ALA-5-14C. However, phenobarbital administration to young weanling animals significantly increased 14CO excretion from glycine-2-14C, but did not result in a change in the activity of hepatic heme oxygenase. The activity of hepatic heme oxygenase does not always reflect in vivo ELB.
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PMID:Developmental changes in bilirubin production in the rat. 641 88

Cimetidine is a well known inhibitor of the heme-containing enzyme cytochrome P-450. We have found that it also inhibits delta-aminolevulinic acid synthase (ALA-S) and microsomal heme oxygenase, the rate-limiting enzymes for heme synthesis and heme degradation respectively. Cytochrome P-450 content was decreased but microsomal heme concentration remained unaltered for a period of 30 min after in vivo cimetidine administration to rats. In vitro incubation of cimetidine with each of the above enzymes revealed no direct effect of cimetidine on ALA-S but about 50% inhibition of heme oxygenase and 20% reduction in cytochrome P-450 content. This suggests that a metabolite of cimetidine inhibits ALA-S activity in vivo, while the drug itself or a metabolite inhibits heme oxygenase both in vivo and in vitro. A rise in ALA-S activity seen after its early inhibition and its return to approximate control values after 60 min suggest a reversible inhibition of ALA-S by a metabolite of cimetidine and may correspond to its clearance from the animal. An elevation in microsomal heme content paralleled the rise in ALA-S activity while microsomal heme oxygenase activity returned to only 65% of control value 60 min after cimetidine treatment. Cytochrome P-450 content did not change after its initial decrease, suggesting that irreversible alteration had occurred.
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PMID:Effect of cimetidine on delta-aminolevulinic acid synthase and microsomal heme oxygenase in rat liver. 654 9


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