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PubMed1977

Isolation and some properties of ribulose-1, 5-bisphosphate carboxylase-oxygenase from red kidney bean primary leaves.

Purification of ribulose-1,5-bisphosphate carboxylase from primary leaves of Phaseolus vulgaris var. Red Kidney with ammonium sulfate precipitation, ion exchange chromatography, and gel filtration resulted in the complete loss of detectable oxygenase activity and the retention of a low velocity and a high K(m) form of both the carboxylase and oxygenase. The polyethylene glycol-6000-purified ribulose-1, 5-bisphosphate oxygenase displayed a broad pH optimum (7.9-9.4) and a high K(m) for O(2) and ribulose 1,5-bisphosphate (0.90 mm and 0.25 mm, respectively). Initiation of the oxygenase reaction with protein rather than ribulose 1,5-bisphosphate resulted in reduced activity. The enzymes prepared by the two purification procedures were electrophoretically different.Etiolated primary leaf tissue exhibited low rates of both carboxylase and oxygenase. Similar developmental kinetic activity was observed for both reactions during greening. Photosynthetic (14)CO(2) fixation was inhibited 95% by 100% N(2) gas during the first 24 hours of greening, but the inhibition was rapidly overcome by 48 to 72 hours of light exposure.

Journal Article↗
PubMed1981

A Sensitive Assay Procedure for Simultaneous Determination of Ribulose-1,5-bisphosphate Carboxylase and Oxygenase Activities.

A sensitive assay procedure is described for the simultaneous determination of ribulose-1,5-bisphosphate (RuBP) carboxylase and oxygenase activities. In this assay, [1-(3)H]RuBP is incubated with (14)CO(2) and O(2). Carboxylation rate is determined from (14)CO(2) incorporation and oxygenation rate is determined from [2-(3)H]glycolate-phosphate production. The assay was found to be suitable at all CO(2) and O(2) concentrations examined, which ranged from 0 to 300 micromolar CO(2) (20 millimolar NaHCO(3)) and 0 to 1.15 millimolar (100%) O(2). In combination with a polarographic assay, the stoichiometry of the RuBP oxygenase reaction was found to be RuBP-O(2)-glycolate phosphate-glycerate phosphate (1:1:1:1).The ratio of soybean (Merr.) RuBP carboxylase and oxygenase activities was measured at various CO(2) and O(2) concentrations and in the presence of several compounds which have been reported to alter differentially the rate of the two reactions. The ratio of the two activities was a linear function of the ratio of the CO(2) and O(2) concentrations. The substrate specificity factor V(c)K(o)/V(o)K(c), which determines relative carboxylase and oxygenase reaction rates as a function of the CO(2) and O(2) concentrations, was found to be 73 in the presence of Mg(2+). Of the several compounds which have been reported to alter differentially the two reactions, we found that only Mn(2+) substitution for Mg(2+) was effective. Compared to Mg(2+), Mn(2+) reduced the K(m)(O(2)) from 690 to 36 micromolar O(2) and reduced the specificity factor to about 4. The K(m)(CO(2)) was about 20 micromolar CO(2) in the presence of both Mg(2+) and Mn(2+). Comparison of reaction rates in the presence of activated and inactivated enzyme allowed a direct determination that both carboxylase and oxygenase activities are similarly activated by CO(2), with an activation equilibrium constant of about 1.3 millimolar NaHCO(3) (27 micromolar CO(2)) at pH 7.85 and 10 millimolar Mg(2+).

Journal Article↗
PubMed1995

Impact of cyclo-oxygenase blockade on juxtamedullary microvascular responses to angiotensin II in rat kidney.

1. Experiments were designed to evaluate the hypothesis that cyclo-oxygenase products modulate the influence of angiotensin II (AII) on the renal juxtamedullary microvasculature of enalaprilat-treated rats. 2. The in vitro blood-perfused juxtamedullary nephron technique was utilized to provide access to afferent arterioles, efferent arterioles and descending vasa recta located in the outer stripe of the outer medulla. 3. Baseline afferent arteriolar diameter was 20.8 +/- 1.9 microns in kidneys subjected to cyclo-oxygenase blockade (1 mumol/L piroxicam), a value significantly lower than that observed in untreated kidneys (26.1 +/- 1.0 microns). Baseline diameters of efferent arterioles and outer medullary descending vasa recta did not differ between untreated and piroxicam-treated groups. 4. Topical application of 1 nmol/L AII reduced blood flow through outer medullary descending vasa recta by 22 +/- 6% in untreated kidneys and by 24 +/- 7% in piroxicam-treated kidneys. 5. In untreated kidneys, AII (0.01-100 nmol/L) produced concentration-dependent afferent and efferent arteriolar constrictor responses of similar magnitudes. Neither afferent nor efferent arteriolar AII responsiveness was significantly altered in piroxicam-treated kidneys, although afferent responses exceeded efferent responses at AII concentrations > or = 10 nmol/L. 6. We conclude that endogenous cyclo-oxygenase products exert a vasodilator influence on juxtamedullary afferent arterioles under baseline conditions. Although cyclo-oxygenase inhibition had little effect on juxtamedullary microvascular responses to AII, the response to high AII concentrations may be modulated by cyclo-oxygenase products in a manner which delicately alters the relative influence of the peptide on pre- vs postglomerular resistances.

Angiotensin II↗
PubMed2005

Dysfunction of the cyclo-oxygenase pathway in the foetoplacental circulation in Type 1 diabetes mellitus.

AIM: In diabetes, perinatal morbidity is significantly increased. This may partly be related to functional changes in the foetoplacental vascular bed. In diabetes models, a defect in the cyclo-oxygenase pathway is a common observation. Therefore, we hypothesized that the human foetoplacental circulation of diabetic patients is characterized by dysfunction of the cyclo-oxygenase pathway, as well. METHODS: We performed ex-vivo perfusions of isolated placental cotyledons from healthy women (n = 14) and from patients with Type 1 diabetes (n = 9). The contribution of cyclo-oxygenase products to foetoplacental vascular tone was quantified by measuring the response to the cyclo-oxygenase inhibitor indomethacin. RESULTS: Baseline foetoplacental arterial pressure was comparable between controls and diabetic women (mean +/- sem, 21.7 +/- 1.2 vs. 24.4 +/- 2.0 mmHg). Maximum foetoplacental arterial pressure at highest dose of indomethacin was 32.8 +/- 3.0 mmHg in controls vs. 27.3 +/- 2.3 mmHg in diabetic women. The indomethacin-induced increase in pressure was reduced in diabetes (2.9 +/- 0.7 vs. 11.2 +/- 2.4 mmHg in controls, P = 0.01). CONCLUSIONS: Under baseline conditions, the net effect of all cyclo-oxygenase products in the foetoplacental vascular bed is vasodilation. In diabetes, this vasodilator effect seems significantly impaired.

Adult↗
PubMed1988

Synergistic enhancement of mitogen responses of human lymphocytes by inhibitors of cyclo-oxygenase and lipoxygenase.

Previously we reported that inhibitors of the enzyme cyclo-oxygenase, which reduce biosynthesis of prostaglandins, may enhance mitogenic responses of human blood lymphoid cells, whereas only marginal effects were observed with 5,8,11-eicosatriynoic acid (ETI), which inhibits 12-lipoxygenase and leukotriene biosynthesis. However, sharply enhanced mitogen responses were observed when lymphoid cells were cultured with both a cyclo-oxygenase inhibitor and ETI, suggesting a synergy between the two drugs. To test whether this is a more general phenomenon occurring between inhibitors of cyclo-oxygenase and lipoxygenase, we have now extended these studies to include the following lipoxygenase inhibitors: cirsiliol; esculetin; 5,8,11,14-eicosatetraynoic acid, and nordihydroguaiaretic acid. The results have shown that any of these drugs combined with a cyclo-oxygenase inhibitor may enhance mitogen responses more than one would expect by summing the effects of the inhibitors tested separately. We conclude that inhibitors of cyclo-oxygenase and lipoxygenase may synergistically enhance mitogen responses of lymphoid cells.

Arachidonate Lipoxygenases↗
PubMed1987

Cyclo-oxygenase and lipoxygenase pathways in cynomolgus and rhesus monkey conjunctiva, anterior uvea and eyelids.

The capacity of cynomolgus and rhesus monkey conjunctiva, anterior uvea and eyelids to synthesize cyclo-oxygenase and lipoxygenase products from arachidonic acid was assessed. Both conjunctiva and eyelid tissues of cynomolgus and rhesus monkeys synthesized detectable amounts of cyclo-oxygenase and lipoxygenase products, indicating the presence of cyclo-oxygenase and 5- and 12-lipoxygenase activities in these tissues. In comparison, cynomolgus anterior uvea synthesized a considerably lesser amount of cyclo-oxygenase products. The cyclo-oxygenase activity was considerably greater than the lipoxygenase activity in cynomolgus and rhesus conjunctiva and eyelids.

Animals↗
PubMed1999

An inhibitor of type-1 cyclo-oxygenase in tissues from human pregnancy.

BACKGROUND: Previous work has shown that first trimester human decidua contains a protein which directly inhibits the activity of type-1 cyclo-oxygenase (COX-1). METHODS: Activity assays for cyclo-oxygenase types I and II were developed. Cell cytosol was prepared from a number of different sources: human placenta and decidua (first and third trimester), two placental cell-lines (BeWo and TCL-1), an endometrial stromal cell-line and K562 erythroleukemia cells. The effects of all cytosols on activity of type I cyclo-oxygenase, and of cytosols from BeWo choriocarcinoma and decidual cells on type II enzyme, were tested. RESULTS: Cytosols from first trimester human placenta, two placental cell-lines, an endometrial stromal cell-line and K562 erythroleukemia cells all inhibited the type I enzyme. The inhibitor protein could not be detected in third trimester human decidual cells after labor, and was present only at very low levels in third trimester decidua prior to the onset of labor. Cytosols from BeWo and decidual cells had no effect on the activity of the type-2 cyclo-oxygenase enzyme. CONCLUSIONS: The inhibitor of type I cyclo-oxygenase was not specific to pregnancy-related tissues, and may be a general regulator of this enzyme. Lower levels of inhibitor were present at term, but the physiological significance of this is unclear. The cytosolic inhibitor appears to be specific to the type I enzyme.

Cell Line↗
PubMed1988

Modulation of natural killing by cyclo- and lipo-oxygenase inhibitors.

The effect on NK activity of two oxygenase inhibitors, indomethacin which is cyclo-oxygenase-specific at 10(-6) M and BW755C which blocks both cyclo- and lipo-oxygenase, has been analysed. The NK activity of human peripheral blood mononuclear cells (PBMC) has been studied in a 18-hr 51Cr-release assay. PBMC were incubated with the drugs for different periods of time before and during NK assay in order to analyse the correlations between the time of incubation and the modulation of NK activity. The results show that the inhibition of the cyclo-oxygenase alone, by indomethacin, enhances the NK activity if the drug is added both during and prior to the assay. In the latter case the enhancement is time dependent, reaching a maximum level after 18 hr of incubation. The simultaneous inhibition of lipo- and cyclo-oxygenase by BW755C has a rather more complex effect. The NK activity is similar to that of untreated cells after 6 hr incubation with BW755C, but is inhibited or greatly enhanced after 4 and 18 hr of incubation, respectively. These effects seem largely independent of the presence of monocytes because they can be observed with non-adherent PBMC (NA-PBMC).

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMedDate not supplied

Control of heme oxygenase and plasma levels of bilirubin by a synthetic heme analogue, tin-protoporphyrin.

The catalytic site of heme oxygenase recognizes metalloporphyrins with central metal atoms other than iron; it favors some of these metalloporphyrins over heme as a potential substrate sometimes by a large factor, permitting the synthetic heme analogue to serve as a potent competitive inhibitor of the heme oxygenase reaction. Since these synthetic metalloporphyrins do not bind molecular oxygen, they are not metabolically degraded by ring rupture and do not add to the body pool of bile pigment. One possible consequence of this competitive inhibition of heme degradation is suppression of bile pigment formation to such a degree that excessive plasma levels of bilirubin may be diminished. That the latter phenomenon occurs was shown for the first time by our study in 1981 (6), and by subsequent investigations in rats, mice, monkeys and man. The compound does not appear to affect the metabolic disposition of preformed bilirubin but inhibits biliary bilirubin excretion derived from the metabolism of endogenous or exogenous heme. Whether some of the effect of Sn-protoporphyrin on naturally occurring or experimentally induced jaundice in animals reflects diversion of heme to nonheme oxygenase-dependent pathways of heme metabolism or whether a pathway which is normally latent becomes activated concurrent with heme oxygenase inhibition is not known. Sn-protoporphyrin is remarkably innocuous in the newborn rat and may prove so in man.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Microassay of heme oxygenase by high-performance liquid chromatography: application to assay of needle biopsies of human liver.

We developed a microassay for heme oxygenase, in which bilirubin (BR) production was measured by HPLC, and compared it to previously reported spectrophotometric methods. The microassay required as little as 5 mg wet human, rat, or chick embryo liver. Using the HPLC assay, values for heme oxygenase activity in extracts (10,000 g supernatant) of normal human liver obtained by needle biopsies were 44 +/- 7 (pmol BR.min-1.mg protein-1). Spectrophotometric assays of homogenates of human liver resulted in low values for heme oxygenase, due to unknown sources of interference. Comparative values of microsomal heme oxygenase activity were 294 +/- 25, 95 +/- 3, and 87 +/- 9 pmol BR.min-1.mg protein-1 for chick, rat, and human livers, respectively.

Animals↗
PubMed1986

Increased rat testicular heme oxygenase activity associated with depressed microsomal heme and cytochrome P-450 levels after repeated administration of human chorionic gonadotropin.

Repeated administration of human chorionic gonadotropin to rats results in a maximal depression of testicular microsomal heme and cytochrome P-450 levels at 24 h, followed by increases that plateau at pretreatment levels by day six. Associated with the depressed levels of microsomal heme and cytochrome P-450 is an increase of testicular microsomal heme oxygenase activity at 12-24 h. Testicular mitochondrial delta-aminolevulinic acid synthase activity was increased at 24 h, and remained elevated throughout the 9-day treatment period. Pretreatment with 1,4,6-androstatrien-3,17-dione, an aromatase inhibitor, failed to prevent the depression of testicular microsomal heme or cytochrome P-450 or increased heme oxygenase activity caused by repeated administration of human chorionic gonadotropin, and administration of estradiol benzoate failed to alter testicular microsomal heme oxygenase activity suggesting that these parameters were not related to altered testicular estrogen content caused by increased aromatase activity. These results suggest that increased testicular heme oxygenase activity is associated with decreased microsomal heme and cytochrome P-450 content during human chorionic gonadotropin-induced desensitization.

5-Aminolevulinate Synthetase↗
PubMed1988

Expression of heme oxygenase gene in rat and human liver.

Developmental changes of microsomal heme oxygenase were studied. In human fetal liver, the enzyme activity was 8 times higher than that detected in the adult liver. On the other hand, adult livers contained 4 times more cytochrome P450 than fetal livers. Elevated heme oxygenase activity in fetal liver was not due to modulators present in the microsomes. Similar to human, rat fetal liver also contained high enzyme activity which appeared to be regulated at the transcriptional level. Hybridization analysis of rat liver RNAs with cDNA for rat heme oxygenase revealed that the level of mRNA for the enzyme was 3-fold higher in the fetus than in the adult. The low cytochrome P450 content may be due in part to the high heme oxygenase activity in fetal livers.

Adult↗
PubMed1984

Effect of cimetidine on delta-aminolevulinic acid synthase and microsomal heme oxygenase in rat liver.

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.

5-Aminolevulinate Synthetase↗
PubMed1985

Hormonal regulation of heme oxygenase induction in avian hepatocyte culture.

The effects of various hormones were examined on the induction of heme oxygenase in monolayer cultures in chick embryo hepatocytes maintained in a chemically defined medium. Addition of insulin to the cultured cells markedly suppressed the activity of basal as well as Co2+-induced heme oxygenase. Treatment of cells with hydrocortisone also suppressed the basal enzyme activity, while the Co2+-induced enzyme activity was enhanced slightly. In contrast, triiodothyronine addition to the culture caused a slight increase of both uninduced and induced levels of the enzyme. This stimulatory effect of triiodothyronine was enhanced significantly by prolonged incubation of cells (48-96 hr) in the serum-free medium. These findings indicate that heme oxygenase synthesis can be substantially altered by changing the hormonal environment of the hepatocytes. Furthermore, the induction of heme oxygenase by Co2+ was inhibited by glucagon, dibutyryl cAMP and theophylline in a dose-dependent manner, suggesting that the enzyme induction may also be controlled by changes in cAMP levels.

5-Aminolevulinate Synthetase↗
PubMed1984

The oxidation of hemins by microsomal heme oxygenase. Structural requirements for the retention of substrate activity.

The substrate specificity of microsomal heme oxygenase from rat liver was studied by introducing systematic structural changes in the array of substituents of the protohemin IX rings. Replacement of the vinyls by methyl groups resulted in hemins which were excellent substrates of the heme oxygenase. Replacement of the 4-vinyl group by a propionic acid chain (harderohemin), decreased substrate activity to 40%. The replacement of the vinyls by formyl residues strongly decreased substrate activity but the hemins were still substrates of heme oxygenase. The oxidation rates of Spirographis hemin and of 2,4-diformyldeuterohemin IX showed a time lag which was absent when isoSpirographis hemin was used as a substrate. This lag could be attributed to the formation of a transient hemiacetal between the 2-formyl group and the alpha-mesohydroxy residue. The isomeric protohemins I, XI, and XIV (Fischer's notation) were examined as possible substrates of microsomal heme oxygenase. In these protohemins the array of substituents of rings A and B was the same as in protohemin IX, but the methyl and propionic acid residues of rings C and D were at different positions from those of protohemin IX. None of them had substrate activity, indicating that the presence of two vicinal propionic acid side-chains at C6 and C7 was necessary for substrate activity. A hemin with only one propionic acid residue at C5 was not a substrate of the enzyme, either. When the propionic acid residues of protohemin IX were replaced by butyric acid residues, substrate activity decreased to 50% (as compared to protohemin IX), while when they were replaced by acetic acid residues, the substrate activity was entirely suppressed. The addition of dimethyl sulfoxide (25 mM) to the incubation mixture enhanced the oxidation of hemins with non-polar substituents in rings A and B by about 35%, while it was without effect on hemins with polar substituents in the same rings.

Animals↗
PubMed1987

Concerning the mechanism for transfer of D-glucuronate from myo-inositol oxygenase to D-glucuronate reductase.

The D-glucuronate product of myo-inositol oxygenase (EC 1.13.99.1) is efficiently reduced by NADPH in the presence of either purified D-glucuronate reductase (EC 1.1.1.19), or reductase that is part of a protein aggregate that also contains the oxygenase. This occurs despite the fact that the maximum concentration of D-glucuronate that could be formed by the oxygenase under the conditions used for the coupled enzyme experiments is 7 microM, and 10 microM externally supplied D-glucuronate (Km = 7.6 mM) does not support any detectable NADPH oxidation under the reaction conditions. The most likely explanation for the results is that the uncyclized aldehyde form of D-glucuronate is the product of the oxygenase reaction, and that it diffuses into solution and is captured by the reductase before it cyclizes to the more stable but less reactive hemiacetal form.

Carbohydrate Dehydrogenases↗
PubMed1988

Inhibitory effect of zinc-protoporphyrin on the induction of heme oxygenase and the associated decrease in cytochrome P-450 content in rats.

Pretreatment of rats with zinc-protoporphyrin, which has shown to be a potent competitive inhibitor of heme oxygenase, resulted in the inhibition of bromobenzene-mediated induction of heme oxygenase and decreases of the cytochrome P-450 content, aminopyrine demethylase and aniline hydroxylase activities. Such an inhibitory effect of zinc-protoporphyrin on the induction of heme oxygenase and concomitant decreases of drug-metabolizing enzymes occurred in a dose-dependent manner with complete inhibition of these effects at a dose of 40 mumol/kg. The effects of zinc-protoporphyrin were also observed in thioacetamide- and BCG-treated rats and ascitic tumor AH 66-bearing rats. Likewise, a decrease of cytochrome b5 content observed under these experimental conditions was also restored significantly by zinc-protoporphyrin. These results strongly suggest that the induction of heme oxygenase is a primarily important early event which consequently leads to the decrease in cytochrome P-450 content and associated enzyme activities.

Aminopyrine N-Demethylase↗
PubMed1981

Zinc . protoporphyrin is a selective inhibitor of heme oxygenase activity in the neonatal rat.

The present study was undertaken to examine the liver, spleen and kidney heme oxygenase activity in the rat, and also to investigate the response of the enzyme to a variety of metalloporphyrin complexes. The enzyme activity in the liver and the kidney of 3--4 day-old rats was several-fold greater than the corresponding values in the adult animals; however, the splenic enzyme activity was markedly depressed in comparison to that of adult rats. During the first 2--3 weeks post-parturation period, the activity of heme oxygenase in the spleen progressively increased, and in 4 weeks approached the adult values. The treatment of the newborn animals with the metalloporphyrin complex. Zn . protoporphyrin-IX, inhibited heme oxygenase activity in the spleen, liver and the kidney. Sn . protoporphyrin treatment also inhibited the activity of the enzyme in the liver and the spleen. The mechanism of the inhibition appeared to be competitive in nature. In contrast, the treatment of the newborn animals with Co . protoporphyrin increased the activity of the enzyme in the tested organs. The treatment of newborn animals with Fe . protoporphyrin (heme) also increased heme oxygenase activity in the spleen and the kidney. In addition, Co . and Fe . protoporphyrin complexes inhibited the activity of delta-aminolevulinate synthetase in the spleen; Sn . protoporphyrin and Zn . protoporphyrin, however, did not alter the activity of this enzyme. The effects of Co . protoporphyrin and Zn. protoporphyrin on the microsomal contents of cytochromes P-450, b5, the total heme, and the microsomal drug metabolism activity in the liver were compared. Zn . protoporphyrin was ineffective in altering the indicated cellular variables. According to these findings Zn . protoporphyrin may be useful as an experimental tool for the selective suppression of heme degradation activity.

5-Aminolevulinate Synthetase↗