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PubMed2000

New insights into physiological and pathophysiological functions of cyclo-oxygenase-2.

During the past few years specific inhibitors of the cyclo-oxygenase-2 enzyme have emerged as important pharmacological tools for treatment of patients with rheumatoid arthritis or osteoarthritis. In comparison to traditional nonsteroidal anti-inflammatory drugs, specific cyclo-oxygenase-2 inhibitors may provide equal efficacy in terms of antiinflammatory and analgesic action, with significantly fewer gastrointestinal side effects. Although cyclo-oxygenase-2 was once regarded as a source of pathological prostanoids, recent studies have indicated that this isoenzyme also fulfills a variety of physiological functions within the organism. The present review assesses recent advances in cyclo-oxygenase-2 research, with particular emphasis on new insights into the biology of this isoenzyme.

Journal Article↗
PubMed2000

Electron flow to oxygen in higher plants and algae: rates and control of direct photoreduction (Mehler reaction) and rubisco oxygenase.

Linear electron transport in chloroplasts produces a number of reduced components associated with photosystem I (PS I) that may subsequently participate in reactions that reduce O2. The two primary reactions that have been extensively studied are: first, the direct reduction of O2 to superoxide by reduced donors associated with PS I (the Mehler reaction), and second, the rubisco oxygenase (ribulose 1,5-bisphosphate carboxylase oxygenase EC 4.1.1.39) reaction and associated peroxisomal and mitochondrial reactions of the photorespiratory pathway. This paper reviews a number of recent and past studies with higher plants, algae and cyanobacteria that have attempted to quantify O2 fluxes under various conditions and their contributions to a number of roles, including photon energy dissipation. In C3 and Crassulacean acid metabolism (CAM) plants, a Mehler O2 uptake reaction is unlikely to support a significant flow of electron transport (probably less than 10%). In addition, if it were present it would appear to scale with photosynthetic carbon oxidation cycle (PCO) and photosynthetic carbon reduction cycle (PCR) activity This is supported by studies with antisense tobacco plants with reduced rubisco at low and high temperatures and high light, as well as studies with potatoes, grapes and madrone during water stress. The lack of significant Mehler in these plants directly argues for a strong control of Mehler reaction in the absence of ATP consumption by the PCR and PCO cycles. The difference between C3 and C4 plants is primarily that the level of light-dependent O2 uptake is generally much lower in C4 plants and is relatively insensitive to the external CO2 concentration. Such a major difference is readily attributed to the operation of the C4 CO2 concentrating mechanism. Algae show a range of light-dependent O2 uptake rates, similar to C4 plants. As in C4 plants, the O2 uptake appears to be largely insensitive to CO2, even in species that lack a CO2 concentrating mechanism and under conditions that are clearly limiting with respect to inorganic carbon supply. A part explanation for this could be that many algal rubsicos have considerably different oxygenase kinetic properties and exhibit far less oxygenase activity in air. This would lead to the conclusion that perhaps a greater proportion of the observed O2 uptake may be due to a Mehler reaction and less to rubisco, compared with C3 plants. In contrast to algae and higher plants, cyanobacteria appear to have a high capacity for Mehler O2 uptake, which appears to be not well coupled or limited by ATP consumption. It is likely that in all higher plants and algae, which have a well-developed non-photochemical quenching mechanism, non-radiative energy dissipation is the major mechanism for dissipating excess photons absorbed by the light-harvesting complexes under stressful conditions. However, for cyanobacteria, with a lack of significant non-photochemical quenching, the situation may well be different.

Animals↗
PubMed2006

Newer cyclo-oxygenase-2 selective inhibitors, other non-steroidal anti-inflammatory drugs and the risk of acute pancreatitis.

BACKGROUND: Case reports have suggested that the use of newer cyclo-oxygenase-2 selective inhibitors may cause acute pancreatitis, but there has been no formal study of the association. AIM: To assess the relationship between the use of cyclo-oxygenase-2 inhibitors and other non-steroidal anti-inflammatory drugs, and risk of acute pancreatitis. METHODS: A population-based case-control study was conducted using hospital discharge and prescription data from Denmark. Using conditional logistic regression with adjustment for multiple covariates, we estimated the relative risk of acute pancreatitis for use of the cyclo-oxygenase-2 inhibitors celecoxib and rofecoxib and for other non-steroidal anti-inflammatory drugs. RESULTS: A total of 3083 cases of acute pancreatitis and 30 830 population controls were identified. For current use the relative risk estimate for celecoxib was 1.4 (95% CI: 0.8-2.3) and for rofecoxib was 1.3 (95% CI: 0.7-2.3). The overall relative risk for other non-steroidal anti-inflammatory drugs was 2.7 (95% CI: 2.4-3.0) with a substantial variation in risk between the individual drugs. The highest relative risk was for diclofenac (odds ratio 5.0, 95% CI: 4.2-5.9) and the lowest for naproxen (odds ratio 1.1, 95% CI: 0.7-1.7). CONCLUSION: Cyclo-oxygenase-2 selective inhibitors are associated with a lower risk of acute pancreatitis than most other non-steroidal anti-inflammatory drugs.

Acute Disease↗
PubMed2006

Expression of cyclo-oxygenase-2 in gastrointestinal carcinoid tumors.

BACKGROUND: Cyclo-oxygenase (COX)-2 overexpression is observed in various neoplasms and COX-2 inhibition has been attempted as prevention and/or therapy in these neoplasms. Carcinoid tumors are thought to arise from neuroendocrine cells and originate mainly in the gastrointestinal tract. Cyclo-oxygenase-2 is reportedly expressed in neuroendocrine cells of normal colorectal mucosa. The role of COX in carcinoids has not previously been investigated. The aim of the present paper was to clarify the expression of COX-1 and -2, and their role in human gastrointestinal carcinoids. METHODS: Expression of COX-1 and -2 was studied immunohistochemically in 38 gastrointestinal carcinoids. Five bronchopulmonary and seven metastatic carcinoids were also examined, for comparison with gastrointestinal carcinoids. The immunohistochemical score (IHS) was calculated from staining intensity and immunoreactive cell population, and ranked according to four grades (negative to strong). RESULTS: Cyclo-oxygenase-2 was expressed in all gastrointestinal carcinoids (weak, 1; moderate, 13; strong, 24) and bronchopulmonary carcinoids (weak, 1; moderate, 4), as well as their metastases (moderate, 3; strong, 4). The IHS of COX-2 in larger tumors was significantly lower than that in smaller tumors. However, the IHS of COX-2 at the advancing tumor edge was significantly higher than that at the centers of tumors >or=10 mm in size. Faint COX-1 expression was detected in only one duodenal, one rectal and four bronchopulmonary carcinoids. CONCLUSIONS: Enhanced COX-2 expression was observed in gastrointestinal as well as bronchopulmonary carcinoids and their metastases, especially at the advancing edges of the tumors. Cyclo-oxygenase-2 may play a role in carcinoid progression.

Adult↗
PubMed1984

Effect of cyclosporin A and inhibitors of arachidonic acid metabolism on blood flow and cyclo-oxygenase products in rat skin allografts.

Using skin blood flow as a measurement of skin graft rejection in rats, it has been shown that in both isografts and allografts the blood flow at first increases above the normal, after which the flow in isografts returns to normal while that in allografts ceases at the onset of rejection. Cyclosporin A (CSA) 5-40 mg kg-1 intramuscularly produced a dose-related inhibition of graft rejection and the pattern of blood flow in the treated allografts became similar to that in isografts in that it remained about 20% above normal throughout the period of treatment. Indomethacin (Indo), inhibitor of cyclo-oxygenase and benoxaprofen (Ben), inhibitor of cyclo-oxygenase and lipoxygenase, caused an enhancement of the onset of rejection and an early cessation of blood flow in allografts. The total content of 4 cyclo-oxygenase products (COP), (prostaglandin E2 (PGE2), PGF2 alpha, 6-oxo-PGF1 alpha and thromboxane B2 (TxB2] increased both in isografts and allografts, but when individual COP were expressed as a percentage of the total, only 6-oxo-PGF1 alpha (the stable metabolite of prostacyclin) increased in allografts. This increased proportion was reduced to normal by a dose of CSA which prolonged graft survival. Indo and Ben partially inhibited COP formation and in particular that of 6-oxo-PGF1 alpha. In addition, CSA caused a dose-related inhibition of the prostacyclin produced by zymosan-activated macrophages. These findings in the rat suggest that prostacyclin is partly responsible for the increase in blood flow in allografts prior to rejection; that CSA inhibits both the recruitment of prostacyclin-producing macrophages and prostacyclin formation directly; and that inhibitors of cyclo-oxygenase enhance skin graft rejection by abrogating the immunoregulatory activity of prostacyclin.

Animals↗
PubMed1995

Mechanisms of pulmonary vasoconstriction and bronchoconstriction produced by PAF in the guinea-pig: role of platelets and cyclo-oxygenase metabolites.

1. The mechanisms of action of platelet activating factor (PAF) in the bronchial and cardiovascular systems have not yet been fully elucidated. In order to characterize better and to ascertain whether the effects of PAF in both these systems may be ascribed to the same mechanisms, we examined the actions of PAF in the heart-lung preparation of guinea-pig (HLP). The role of platelets and of cyclo-oxygenase metabolites was investigated. 2. In HLPs perfused with autologous blood, bolus injections of PAF (4-32 ng) produced major effects at the pulmonary vascular and bronchial levels. Both dose-related pulmonary vascular hypertension and bronchoconstriction produced by PAF were diminished to the same extent (46% and, respectively, 47%) when HLPs were perfused with a medium consisting of homologous red blood cells suspended in physiological solution containing 3.5% dextran (RBC). This suggests that the effects of PAF partially depend on the presence of formed elements. 3. When indomethacin (30 microM) was added to the perfusing blood, the dose-response curve for the pulmonary hypertensive responses produced by PAF was strongly reduced (90%) in comparison to control preparations, whereas the bronchoconstrictor effects of PAF were only partially diminished (23%). These data constitute direct evidence that products of the cyclo-oxygenase pathway exert a major role in the vascular, rather than in the bronchial actions of PAF. 4. In HLPs perfused with RBC containing indomethacin (30 microM), the pulmonary vascular hypertensive responses produced by PAF were almost completely abolished, thus indicating that cyclo-oxygenase products from tissues are involved in these effects. Conversely, PAF administration continued to cause dose-related bronchoconstrictor responses that were reduced only partially in comparison with HLPs perfused with RBC in the absence of the cyclo-oxygenase inhibitor. This implies that PAF also has direct action on the bronchoconstriction evoked.5. At the cardiac level, administration of PAF in HLPs perfused with blood caused a dose-related increase in right atrial pressure accompanied by a decrease in left atrial pressure and cardiac output,which were completely suppressed or attenuated by the absence of formed elements and the addition of indomethacin. This suggests that the progressive heart impairment is secondary to the severe pulmonary hypertension induced by PAF.6. The results of this study performed in the heart-lung preparation of the guinea-pig, which made it possible to simultaneously record cardiovascular and bronchial parameters, indicate that various components are involved in the responses produced by PAF. It is suggested that different mechanisms depending on the relative contribution of these components may account for the PAF-induced effects at the pulmonary vascular and airway levels.

Animals↗
PubMed1995

Effects of the novel anti-inflammatory compounds, N-[2-(cyclohexyloxy)-4-nitrophenyl] methanesulphonamide (NS-398) and 5-methanesulphonamido-6-(2,4-difluorothio-phenyl)-1-inda none (L-745,337), on the cyclo-oxygenase activity of human blood prostaglandin endoperoxide synthases.

1. We have evaluated the selectivity of ketoprofen and two novel nonsteroidal anti-inflammatory drugs, N-[2-(cyclohexyloxy)-4-nitrophenyl]methanesulphonamide (NS-398) and 5-methanesulphonamido-6-(2,4-difluorothiophenyl)-1-indano ne (L-745,337), in inhibiting the cyclo-oxygenase activity of prostaglandin endoperoxide synthase-2 (PGHS-2) vs PGHS-1 in human blood monocytes and platelets, respectively. 2. Heparinized whole blood samples were drawn from healthy volunteers pretreated with aspirin, 300 mg 48 h before sampling, to suppress the activity of platelet PGHS-1 and incubated at 37 degrees C for 24 h with increasing concentrations of the test compounds in the presence of lipopolysaccharide (LPS, 10 micrograms ml-1). Immunoreactive PGE2 levels were measured in plasma by a specific radioimmunoassay as an index of the cyclo-oxygenase activity of LPS-induced monocyte PGHS-2. 3. The effects of the same inhibitors on platelet PGHS-1 activity were assessed by allowing whole blood samples, drawn from the same subjects in aspirin-free periods, to clot at 37 degrees C for 1 h in the presence of the compounds and measuring immunoreactive thromboxane B2 (TXB2) levels in serum by a specific radioimmunoassay. 4. Under these experimental conditions, ketoprofen enantioselectively inhibited the cyclo-oxygenase activity of both PGHS-1 and PGHS-2 with equal potency (IC50 ratio: approx. 0.5 for both enantiomers), while L-745,337 and NS-398 achieved selective inhibition of monocyte PGHS-2 (IC50 ratio: > 150). L-745,337 and NS-398 did not affect LPS-induced monocyte PGHS-2 biosynthesis to any detectable extent. 5. We conclude that L-745,337 and NS-398 are selective inhibitors of the cyclo-oxygenase activity of human monocyte PGHS-2. These compounds may provide adequate tools to test the contribution of this novel pathway of arachidonate metabolism to human inflammatory disease.

Adult↗
PubMed1995

Enhancement by cyclo-oxygenase inhibitors of platelet-activating factor production in thapsigargin-stimulated macrophages.

1. Thapsigargin stimulated the accumulation of cell-associated platelet-activating factor (PAF) and extracellular prostaglandin E2 (PGE2) in rat peritoneal macrophages. PAF in the conditioned medium was less than the detectable amount. To obtain further insight into the mechanism of PAF accumulation, the role of PGE2 in PAF accumulation was investigated. 2. When macrophages were incubated in medium containing thapsigargin (30 ng ml(-1), 46.1 nM) and cyclo-oxygenase inhibitors such as indomethacin, naproxen or ibuprofen, the PAF content of the cells at 10 min was increased in a concentration-dependent manner in accordance with inhibition of PGE2 production. The stimulation by thapsigargin, cyclo-oxygenase inhibitors did not increase PAF accumulation. 3. In thapsigargin-stimulated macrophages, when PGE2(10(-7) M) was added to the medium, the cyclo-oxygenase inhibitor-induced stimulation of PAF accumulation at 10 min was markedly inhibited. 4. The accumulation of PAF induced by thapsigargin alone at 10 min was inhibited by exogenous PGE2 (10(-8) and 10(-7) M), or arachidonic acid (10(-6) and 10(-5) M) in accordance with the increase in PGE2 production. 5. The accumulation of PAF induced by thapsigargin alone or by thapsigargin and indomethacin (10(-6) M) was inhibited by dibutyryl cyclic AMP. 6. These results indicate that the concurrently produced PGE2 in thapsigargin-stimulated macrophages down-regulates PAF accumulation by increasing intracellular cyclic AMP levels, and that cyclo-oxygenase inhibitors increase PAF accumulation by inhibiting PGE2 production.

Animals↗
PubMed1996

Induction of prostaglandin endoperoxide synthase-2 in human monocytes associated with cyclo-oxygenase-dependent F2-isoprostane formation.

1. The isoprostane 8-epi-prostaglandin (PG)F2 alpha is produced by free radical-catalyzed peroxidation of arachidonic acid. It may also be formed as a minor product of the cyclo-oxygenase activity of platelet PGH synthase (PGHS)-1. We investigated 8-epi-PGF2 alpha production associated with induction of the human monocyte PGHS-2 and its pharmacological modulation. 2. Heparinized whole blood samples were drawn from healthy volunteers, 48 h following oral dosing with aspirin 300 mg to suppress platelet cyclo-oxygenase activity. One ml aliquots were incubated with lipopolysaccharide (LPS: 0.1-50 micrograms ml-1) for 0-24 h at 37 degrees C. PGE2 and 8-epi-PGF2 alpha were measured in separated plasma by radioimmunoassay and enzyme immunoassay techniques. 3. Levels of both eicosanoids were undetectable (i.e. < 60 pg ml-1) at time 0. LPS induced the formation of PGE2 and 8-epi-PGF2 alpha in a time- and concentration-dependent fashion, coincident with the induction of PGHS-2 detected by Western blot analysis of monocyte lysates. After 24 h at 10 micrograms ml-1 LPS, immunoreactive PGE2 and 8-epi-PGF2 alpha averaged 10,480 +/- 4,643 and 295 +/- 140 pg ml-1 (mean +/- s.d., n = 6), respectively. 4. Dexamethasone and 5-methanesulphonamido-6-(2,4-difluorothiophenyl)-1-indano ne (L-745,337), a selective inhibitor of the cyclo-oxygenase activity of PGHS-2, reduced PGE2 and 8-epi-PGF2 alpha production in response to LPS. 5. Isolated monocytes produced PGE2 and 8-epi-PGE2 alpha in response to LPS (10 micrograms ml-1) in a time-dependent fashion. Monocyte PGE2 and 8-epi-PGF2 alpha production was largely prevented by dexamethasone (2 microM) and cycloheximide (10 micrograms ml-1) in association with suppression of PGHS-2 but not of PGHS-1 expression. 6. We conclude that the induction of PGHS-2 in human monocytes is associated with cyclo-oxygenase-dependent generation of the vasoconstrictor and platelet-agonist 8-epi-PGF2 alpha.

Adult↗
PubMed1994

Terephthalate 1,2-dioxygenase system from Comamonas testosteroni T-2: purification and some properties of the oxygenase component.

Comamonas testosteroni T-2, grown in terephthalate (TER)-salts medium, synthesizes inducible enzymes that convert TER to (1R,2S)-dihydroxy-3,5-cyclohexadiene-1,4-dicarboxylic acid (DCD) and protocatechuate (PC). Anion-exchange chromatography of cell extracts yielded two sets of fractions, R and Z, that were necessary for oxygenation of TER to DCD; we termed this activity the TER dioxygenase system (TERDOS). An NAD(+)-dependent DCD dehydrogenase, which converted DCD to PC, overlapped all fractions R. No significant purification from fraction R, which contained an NADH-dependent reductase function(s) of TERDOS, was attained. Fraction Z, at the end of the gradient, contained essentially one protein, which was further purified by hydrophobic interaction chromatography. This component, Z, had the UV-visible spectrum and electron paramagnetic resonance characteristics of a Rieske [2Fe-2S] protein and was considered to be the oxygenase. M(r)s of about 126,000 for oxygenase Z under native conditions were observed. Oxygenase Z consisted of two subunits, alpha and beta, with M(r)s of 49,000 and 18,000, respectively, under denaturing conditions. We presume that this oxygenase has an alpha 2 beta 2 structure. The sequences of the N-terminal amino acids of each subunit were determined. The activity of the purified enzyme was enhanced about fivefold by addition of Fe2+. In the presence of O2, NADH, and fraction R, component Z catalyzed the stoichiometric transformation of TER to PC, with the intermediate formation of DCD. The reaction was confirmed as a dioxygenation when we observed incorporation of two oxygen atoms from 18O2 into PC. The substrate range of TERDOS appeared to be narrow; apart from TER, only 2,5-dicarboxypyridine and 1,4-dicarboxynaphthalene (of 11 compounds tested) were converted to a product.

Biodegradation, Environmental↗
PubMed1983

Biosynthesis of lipoxygenase and cyclo-oxygenase products from [14C]-arachidonic acid by human colonic mucosa.

The human colon synthetises several prostanoids which may have a role in inflammatory bowel diseases. As lipoxygenase products of arachidonate metabolism have been implicated in inflammatory processes, we have now investigated the formation of both lipoxygenase and cyclo-oxygenase metabolites from [14C]-arachidonic acid [(14C]-AA) by human colonic tissue. Homogenates of human colonic mucosa were incubated with [14C]-AA and after extraction into diethyl ether, separated by thin layer chromatography using two solvent systems that allowed resolution of cyclo-oxygenase and lipoxygenase products. The predominant cyclo-oxygenase products, as identified by their chromatographic mobility, were PGE2 greater than PGF2 alpha greater than PGD2 greater than TXB2 greater than 6-keto-PGF1 alpha. The formation of these products was inhibited both by indomethacin (1-10 microM) and the dual pathway inhibitor, BW755C (1-30 microM). The predominant lipoxygenase products formed, which had the chromatographic mobility of 11-, 12-, 15-HETE (which ran together) were inhibited by BW755C (19 microM) but not by indomethacin (3 microM). Further resolution of this TLC band, performed using normal phase HPLC, indicated that both 12-HETE and 15-HETE were major lipoxygenase products formed by human colonic homogenate. The present findings indicate that human colonic tissue can convert [14C]-AA into lipoxygenase as well as cyclo-oxygenase products and support the suggestion that lipoxygenase products may have a role in inflammatory bowel disease.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1988

In vivo and in vitro effects of zinc oxide-eugenol (ZOE) on biosynthesis of cyclo-oxygenase products in rat dental pulp.

To determine the in vivo effects of a zinc oxide-eugenol mixture (ZOE) on the cyclo-oxygenase system in dental pulp, we used radioimmunoassay to measure the levels of prostaglandin E2 (PGE2), 13,14-dihydro-15-keto-PG (DHK-PG), thromboxane B2 (TXB2), and 6-keto-PGF1 alpha in the dental pulp of rats. When the dental pulp was irritated by a hole made in the dentin of the mandibular incisors without use of any coolants, the levels of these cyclo-oxygenase products in the pulp were increased to, respectively, 2.8, 1.7, 10.0, and 2.6 times those in the normal pulp at six hr after treatment. In contrast, these increases in cyclo-oxygenase products disappeared immediately when the artificial cavity in the dentin was filled with ZOE (P/L; 1 g/0.25 mL), but were not altered when the cavity was filled with zinc oxidewater (ZOW, 1 g/1.5 mL). Most of the eugenol portion of ZOE was released into the pulp within two hr after the cavity was filled with ZOE. The maximal eugenol content was 35 pmol per mg of pulp. Furthermore, when the cavity was filled either with ZOE or by the addition of 10 mumol/L eugenol to the pulp homogenate, biosynthesis of 14C-6-keto-PGF1 alpha, PGF2 alpha, and PGE2 from 14C-arachidonic acid in the homogenate was inhibited. These results suggest that eugenol released from ZOE in the cavity prepared in the dentin inhibited the biosynthesis of cyclo-oxygenase products during pulp irritation.

Animals↗
PubMed1990

Platelet activating factor stimulates cyclo-oxygenase activity in guinea pig eosinophils. Concerted biosynthesis of thromboxane A2 and E-series prostaglandins.

The effect of platelet activating factor (PAF) on the generation of cyclo-oxygenase-derived arachidonic acid metabolites was examined on purified eosinophils harvested from the peritoneal cavity of male guinea pigs. PAF produced a concentration-dependent increase in the amount of immunoreactive thromboxane B2 (TXB2) and PGE1/E2 released from these inflammatory cells at a relative molar ratio of 30:1. The EC50 of PAF was 20 to 40 nM and maximum stimulation (4.5-fold) of both prostanoids occurred at 1 microM PAF. The ability of PAF to generate TXA2 was rapid (t 1/2 = 9 s), transient (40 s), noncytotoxic, and noncompetitively antagonized by the PAF-receptor blocking drug, WEB 2086. On an equimolar (100 nM) basis, PAF was significantly more effective than C5a, fMLP, and PMA at stimulating TXB2 release but markedly less potent than the calcium ionophore, calcimycin. Pretreatment of eosinophils with the cyclo-oxygenase inhibitor flurbiprofen (8 microM for 5 min) abolished the ability of PAF to promote both TXB2 and PGE1/E2 release. Likewise, dazmegrel (50 microM for 5 min), a selective inhibitor of thromboxane synthetase, abolished PAF-stimulated TXB2 release but markedly augmented the elaboration of PGE1/E2. Inhibition of cyclo-oxygenase with flurbiprofen affected neither the ability of PAF to elevate the intracellular calcium ion concentration (measured by fura-2 fluorescence) nor its appetency to generate superoxide anions at any PAF concentration examined. It is concluded that activation of guinea pig eosinophils by PAF is receptor-mediated and independent of the concomitant generation of cyclo-oxygenase-derived excitatory prostanoids. Inasmuch as TXA2 may contribute to the pathogenesis of bronchial hyperreactivity, then these data implicate the eosinophil as a potential source of this lipid mediator.

Animals↗
PubMedDate not supplied

The duration of exposure of microsomal preparations to cadmium or zinc in vitro influences the inhibition of mono-oxygenases.

Preincubation of guinea pig hepatic, pulmonary, or adrenal microsomes with cadmium or zinc decreased mono-oxygenase [benzo(a)pyrene hydroxylase, benzphetamine demethylase] activities. Addition of the same concentrations of the metals to the microsomal suspensions after the preincubation period had little or no effect on enzyme activities. The decline in mono-oxygenase activities produced by cadmium or zinc was dependent on the length of the preincubation period as well as the concentration of metal present during the preincubation. In addition, the preincubation effects of both metals were temperature dependent; at temperatures between 4 and 37 degrees C, loss of enzyme activity increased with increasing temperature. Cadmium and zinc produced greater decreases in mono-oxygenase activities in pulmonary and adrenal microsomes than in hepatic microsomes. The results indicate that the duration of exposure of hepatic and extrahepatic microsomal preparations to cadmium or zinc in vitro is an important determinant of effects on mono-oxygenases.

Adrenal Glands↗
PubMed1993

Fatty acid oxygenase activity of human hair roots.

The extent to which fatty acid oxygenases are activated in the normal epidermis is not known. Characterization of the regio- and stereospecificity of the monohydroxylated derivatives of arachidonic and linoleic acid produced by human hair roots is needed to define the enzymatic origin of these compounds and to define a possible role for fatty acid oxygenases in growth, differentiation, and pathology of human hair. Hair roots epilated from normal human volunteers were incubated with radiolabeled arachidonic acid or linoleic acid and the monohydroxylated derivatives produced in vitro were characterized. Incubation of hair roots with 14C]arachidonic acid resulted in the production of 15(S)-[14C]hydroxyeicosatetraenoic acid and 12(S,R)-[14C]hydroxyeicosatetraenoic acid (mean S/R ratio, 2.5). 13(S)-[14C]hydroxyoctadecadienoic acid was the principal product of incubations with [14C]linoleic acid. No radiolabeled products were derived from incubations with heat-denatured hair roots. The fatty acid oxygenase activity of anagen hair roots was inhibited by nordihydroguaiaretic acid and was greatest in the hair root bulb. The strict S-stereospecificity and the regiospecificity of the n-6 oxygenase are strong evidence for the presence of a 15-lipoxygenase in human hair roots, similar to that identified in cultured human keratinocytes. The stereospecificity of the 12-HETE produced by human hair roots is not compatible with the sole action of 12-lipoxygenase.

Arachidonate 12-Lipoxygenase↗
PubMedDate not supplied

Sn-protoporphyrin lowers serum bilirubin levels, decreases biliary bilirubin output, enhances biliary heme excretion and potently inhibits hepatic heme oxygenase activity in normal human subjects.

Sn-protoporphyrin, a potent competitive inhibitor of heme oxygenase, the rate-limiting enzyme in the degradation of heme to bile pigment, was administered to 10 normal volunteers: 8 males and 2 females. A significant decrease in the levels of serum (mean decrease; 38%) and biliary bilirubin (mean decrease: 47%) was demonstrated in all 10 subjects. The decrease in these parameters lasted for a minimum of 4 days after administration of the metalloporphyrin. Sn-protoporphyrin also facilitated the excretion of endogenous heme in bile during the 24- to 48-hr period following administration of the compound. The metalloporphyrin was rapidly cleared from plasma with a half-life of 3.4 hr. A small amount (3 to 6%) of Sn-protoporphyrin was excreted in both urine and bile. The activity of microsomal heme oxygenase was measured in five human liver samples freshly obtained at the time of cholecystectomy and varied from approximately 2 to 4 nmoles bilirubin formed per mg protein per hour. The addition of Sn-protoporphyrin to microsomal heme oxygenase isolated from these liver samples resulted in a dose-dependent decrease in the activity of this enzyme at concentrations of the metalloporphyrin in the range of 10(-7) to 10(-9) M. The findings reported here provide strong evidence that the suppression of biliary and serum bilirubin levels and the enhancement of heme excretion in the bile of the normal volunteers examined in this study were due to inhibition of physiological rates of heme oxidation activity by the synthetic heme analog, Sn-protoporphyrin.

Adult↗
PubMed2005

Acetylcarnitine induces heme oxygenase in rat astrocytes and protects against oxidative stress: involvement of the transcription factor Nrf2.

Efficient functioning of maintenance and repair processes seem to be crucial for both survival and physical quality of life. This is accomplished by a complex network of the so-called longevity assurance processes, under control of several genes termed vitagenes. These include members of the heat shock protein system, and there is now evidence that the heat shock response contributes to establishing a cytoprotective state in a wide variety of human conditions, including inflammation, neurodegenerative disorders, and aging. Among the various heat shock proteins, heme oxygenase-1 has received considerable attention; it has been recently demonstrated that heme oxygenase-1 induction, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. Acetyl-L-carnitine is proposed as a therapeutic agent for several neurodegenerative disorders. Accordingly, we report here that treatment of astrocytes with acetyl-L-carnitine induces heme oxygenase-1 in a dose- and time-dependent manner and that this effect was associated with up-regulation of heat shock protein 60 as well as high expression of the redox-sensitive transcription factor Nrf2 in the nuclear fraction of treated cells. In addition, we show that addition of acetyl-L-carnitine to astrocytes, prior to proinflammatory lipopolysaccharide- and interferon-gamma-induced nitrosative stress, prevents changes in mitochondrial respiratory chain complex activity, protein nitrosation and antioxidant status induced by inflammatory cytokine insult. Given the broad cytoprotective properties of the heat shock response, molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. Particularly, manipulation of endogenous cellular defense mechanisms via acetyl-L-carnitine may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration. We hypothesize that maintenance or recovery of the activity of vitagenes may delay the aging process and decrease the risk of age-related diseases.

Acetylcarnitine↗
PubMed2005

Heme, heme oxygenase and ferritin in vascular endothelial cell injury.

Iron-derived reactive oxygen species are implicated in the pathogenesis of numerous vascular disorders including atherosclerosis, microangiopathic hemolytic anemia, vasculitis, and reperfusion injury. One abundant source of redox active iron is heme, which is inherently dangerous when released from intracellular heme proteins. The present review concerns the involvement of heme in vascular endothelial cell damage and the strategies used by endothelium to minimize such damage. Exposure of endothelium to heme greatly potentiates cell killing mediated by polymorphonuclear leukocytes and other sources of reactive oxygen. Free heme also promotes the conversion of low-density lipoprotein (LDL) into cytotoxic oxidized products. Only because of its abundance, hemoglobin probably represents the most important potential source of heme within the vascular endothelium; hemoglobin in plasma, when oxidized, transfers heme to endothelium and LDL, thereby enhancing cellular susceptibility to oxidant-mediated injury. As a defense against such toxicity, upon exposure to heme or hemoglobin, endothelial cells up-regulate heme oxygenase-1 and ferritin. Heme oxygenase-1 is a heme-degrading enzyme that opens the porphyrin ring, producing biliverdin, carbon monoxide, and the most dangerous product - free redox active iron. The latter can be effectively controlled by ferritin via sequestration and ferroxidase activity. Ferritin serves as a protective gene by virtue of antioxidant, antiapoptotic, and antiproliferative actions. These homeostatic adjustments have been shown effective in the protection of endothelium against the damaging effects of exogenous heme and oxidants. The central importance of this protective system was recently highlighted by a child diagnosed with heme oxygenase-1 deficiency, who exhibited extensive endothelial damage.

Animals↗