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-Tocopherol, but not 
-tocopherol, decreases proinflammatory eicosanoids and inflammation damage in rats
Division of Biochemistry and Molecular Biology, University of California, Berkeley; and Children's Hospital Oakland Research Institute, Oakland, California, USA
1Correspondence: CHORI, 5700 Martin Luther King Jr. Way, Oakland, CA 94609-1673, USA. E-mail: bnames{at}uclink4.berkeley.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-Tocopherol (T), the major form of vitamin E in U.S. diets, and its physiological metabolite 2, 7, 8-trimethyl-2-(ß-carboxyethyl)-6-hydroxychroman (-CEHC), in contrast to 
-tocopherol (T), the primary vitamin E in supplements, inhibit cyclooxygenase-catalyzed synthesis of prostaglandin E2 (PGE2) in activated macrophages and epithelial cells. Here we report that in carrageenan-induced inflammation in male Wistar rats, administration of T (33 or 100 mg/kg) and -CEHC (2 mg/pouch), but not T (33 mg/kg), significantly reduced PGE2 synthesis at the site of inflammation. T, but not T, significantly inhibited the formation of leukotriene B4, a potent chemotactic agent synthesized by the 5-lipoxygenase of neutrophils. Although T had no effect on neutrophil infiltration, it significantly attenuated the partial loss of food consumption caused by inflammation-associated discomfort. Administration of T led consistently to a significant reduction of inflammation-mediated increase in 8-isoprostane, a biomarker of lipid peroxidation. T at 100 mg/kg reduced TNF- (65%;P=0.069), total nitrate/nitrite (40%;P=0.1), and lactate dehydrogenase activity (30%;P=0.067). Collectively, T inhibits proinflammatory PGE2 and LTB4, decreases TNF-, and attenuates inflammation-mediated damage. These findings provide strong evidence that T shows anti-inflammatory activities in vivo that may be important for human disease prevention and therapy.—Jiang, Q., Ames, B. N. -Tocopherol, but not -tocopherol, decreases proinflammatory eicosanoids and inflammation damage in rats.
Key Words: vitamin E • -tocopherol metabolite • prostaglandin E2 • leukotriene B4 • TNF-alpha
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, cardiovascular diseases (2)
, and neurodegenerative disorders (3)
. During inflammation, various eicosanoids derived from arachidonic acid (AA) play a key role in mediating inflammatory response (4)
. For instance, prostaglandin E2 (PGE2), which is synthesized from cyclooxygenase (COX)-catalyzed oxidation of AA, is believed to cause pain and fever (4
, 5)
, as well as activate cytokine formation (6)
. PGE2 can be produced by either the constitutive form (COX-1) or the inducible form (COX-2) of cyclooxygenase (7)
. In most inflammatory conditions, COX-2 is up-regulated and is the primary enzyme responsible for the formation of proinflammatory PGE2 (7)
. Leukotriene B4 (LTB4), another oxidized product derived from AA through the 5-lipoxygenase-catalyzed pathway, is one of the most potent chemotactic agents (8)
. Because of the central roles of PGE2 and LTB4, COX-2 and 5-lipoxygenase have been recognized as key targets for drug therapy in inflammation-associated diseases. In particular, COX-2 inhibitors, which are classified as nonsteroidal anti-inflammatory drugs (NSAIDs), have proved effective in attenuating inflammatory response and are beneficial for certain inflammation-associated diseases (9)
.
We recently found that -tocopherol (T), the major form of vitamin E in the U.S. diet, and its physiological metabolite, 2, 7, 8-trimethyl-2-(ß-carboxyethyl)-6-hydroxychroman (-CEHC), inhibit COX-2-catalyzed formation of PGE2, as assayed in lipopolysaccharide-stimulated macrophage and interlukin-1ß-activated epithelial cells (10)
. This indicates that T and its metabolite may have anti-inflammatory properties similar to those of NSAIDs. In contrast, -tocopherol (T), the predominant form of vitamin E in the tissues and most supplements, is much less effective in this regard (10)
. The present study is aimed to test whether T and its metabolite inhibit PGE2 and other proinflammatory eicosanoids in an air pouch model where inflammation is induced by a single injection of carrageenan (11)
. For comparison, the effect of T was tested. In addition to eicosanoids, the effects of T on the generation of tumor necrosis factor- (TNF-), an inflammatory cytokine, reactive nitrogen oxide, and oxidative damage were also investigated.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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T (
99%) and T (95%-97%) were purchased from Acros Organics (Fairlawn, NJ, USA) or Fluka (Milwaukee, WI, USA). -CEHC (
98%) was from Cayman Chemicals (Ann Arbor, MI, USA). Carrageenan, -tocopherol acetate, and all other chemicals were from Sigma (St. Louis, MO, USA).
Carrageenan-induced inflammation in the air pouch model
The animal use protocol was approved by the animal care committee at the Children's Hospital Oakland Research Institute and strictly followed. Male Wistar rats (250–330 g) (Charles River, CA, USA) were caged singly and routinely fed ad libitum with Purina Chow with free access to tap water. An air pouch was created by a subcutaneous injection of 12 mL sterile air into the intrascapular area of the rat's back. Thirty hours later, 2 mL of 0.5% carrageenan or phosphate-buffered saline (PBS) (controls) was injected into the air pouch. To test the effect of -CEHC, which is water soluble, 2 mg per pouch was dissolved in PBS and injected directly into the pouch right before carrageenan injection. Six hours after the induction of inflammation, animals were killed and the pouch fluid was collected to evaluate the inflammatory response (see below). In the experiments with tocopherols, animals were fed with T (33 or 100 mg/kg) or T (33 mg/kg), continuously for 3 days by gavage using 0.5 mL tocopherol-stripped corn oil (Dyets Inc., Bethlehem, PA, USA) as the vehicle, before injection of carrageenan. Control animals received the same volume of tocopherol-stripped corn oil. Twenty hours after the injection of carrageenan (0.5%, 2 mL), rats were killed and pouch fluid was collected by lavage with Hanks-buffered saline solution containing 0.004% heparin but no Ca2+/Mg2+. After a brief centrifugation, the supernatant was collected and frozen immediately on dry ice for the measurement of PGE2, LTB4, and TNF-, etc. Total cells were counted by a Coulter counter or hemocytometer.
Measurement of T and T
Plasma and exudate T and T were extracted using a mixture of methanol/hexane (2:5, v/v) in the presence of 0.8 mM butylated hydroxytoluene (BHT) (12)
. After brief centrifugation at 4ºC, the top hexane layer was dried under N2 and the residue was resuspended in ethanol. Tocopherols were separated on a 150 x 4.6 mm, 5 µm SupelcosilTM LC-18-DB column (Supelco, Bellefonte, PA, USA) and eluted with 95:5 (v/v) methanol/0.1M lithium acetate (final 25 mM, pH 4.75) at a flow rate of 1.3 mL/min. Tocopherols were monitored by coulometric detection (Model Coulochem II, ESA Inc., Chelmsford, MA, USA) at 300 (upstream) and 500 mV (downstream electrode) using a Model 5011 analytical cell.
Quantification of -CEHC
The sample preparation procedure was modified from a published method (13)
. Briefly, 200 µL of plasma was diluted into the same volume of cold PBS with 5% ethanol and the lipid components were removed by an extraction with 0.5 mL hexane containing 0.8 mM of BHT. After aspiration of the hexane layer, the remaining aqueous phase was acidified to pH 3–4 with acetic acid. -CEHC was then extracted twice with 1 mL ethyl acetate containing 0.8 mM BHT. The combined ethyl acetate layer was evaporated under N2 and the residue was resuspended in the HPLC elute solvent (see below). -CEHC was injected onto a 150 x 4.6 mm, 5 µm SupelcosilTM LC-18-DB column (Supelco) and eluted with 10 mM lithium acetate (pH 4.3) containing 35% acetonitrile at a flow rate of 1.0 mL/min. -CEHC was monitored by coulometric detection (Model Coulochem II, ESA Inc.) at 300 mV using a Model 5011 analytical cell.
Measurement of PGE2, LTB4, 8-isoprostane, LDH, and TNF- in the exudate
For measurement of PGE2, LTB4, and 8-isoprostane, the exudate fluid was mixed vigorously with 2 mL methanol to precipitate proteins and with 5 mL hexane to remove lipids. After a brief centrifugation and aspiration of the hexane layer, the methanol layer was removed and evaporated under N2. PGE2, LTB4, and 8-isoprostane were measured using the corresponding ELISA kits from Cayman Chemicals. TNF- and lactate dehydrogenase (LDH) in the exudate were measured directly using an ELISA kit from R&D (Minneapolis, MN, USA) and an analytical kit from Roche (Indianapolis, IN, USA), respectively.
Quantitation of total NO2- and NO3-
The total amount of nitrate and nitrite in the exudate was measured using the Model 280 nitric oxide analyzer (NOATM) (Sievers Instruments, Inc., Boulder, CO, USA). Nitrite and nitrate in the exudate were reduced by vanadium (III) to nitric oxide, which was then measured by a red-sensitive photomultiplier tube after being converted by ozone to chemiluminescent reactive nitrogen dioxide. Nitrite and nitrate were quantified based on a standard curve from nitrate established under identical conditions.
Statistics
A nonpaired Student’s t test was performed in all the data analyses. Data are expressed as mean ± SE.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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T and its major metabolite, -CEHC, but not T, significantly inhibited proinflammatory eicosanoids at the site of inflammation
. In this model, an injection of air into the intrascapular area resulted in the formation of a connective tissue cavity lined mainly with macrophages and fibroblasts (11
, 15)
. These cells play a key role in the inflammatory response (11
, 14
, 15)
. A single injection of carrageenan caused a potent localized inflammation as indicated by a marked increase in white cell infiltration, eicosanoid formation, and tissue damage (11)
. To study the effect of -CEHC on eicosanoid synthesis and neutrophil infiltration, it (1 mg/mL, 2 mL in PBS) was injected directly into the air pouch right before the injection of carrageenan. Since the retention of -CEHC is relatively short (16)
, its effect was evaluated 6 h after the induction of inflammation. Administration of -CEHC significantly reduced PGE2 (29%, P<0.05) in the pouch (Fig. 1
A), which is consistent with our previous observations in vitro (10)
. At this dose, -CEHC also inhibited LTB4 and neutrophil infiltration (Fig. 1B, C
), though not significantly.
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To test the effects of tocopherols, T or T dissolved in tocopherol-stripped corn oil was continuously administrated by gavage for 3 days before the induction of inflammation. Effects were evaluated at 20 h after carrageenan injection, when cell infiltration had reached a maximum in the pouch (data not shown). At a dose of 33 mg/kg, T, but not T, significantly reduced the proinflammatory PGE2 (46%, P<0.05; Fig. 2
A) and LTB4 (70%, P<0.05; Fig. 2B
), a potent chemotactic eicosanoid produced by the 5-lipoxygenase in neutrophils. At a higher dose (100 mg/kg), T showed an inhibitory potency against PGE2 (51%, P<0.05) and LTB4 similar to the lower dose. Despite the inhibitory effects on PGE2 and LTB4, T did not affect neutrophil infiltration (Fig. 2C
).
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T reduced TNF- and total nitrite and nitrate at the higher dose of 100 mg/kg
Besides eicosanoids, we have investigated the effects of T on TNF-, an important inflammation mediator, and total nitrite and nitrate, an index of the generation of reactive nitrogen oxides (Fig. 3
). At the lower dose of 33 mg/kg, T nonsignificantly inhibited TNF- (51%, P=0.29) but had no effect on total nitrate and nitrite. At the higher dose of 100 mg/kg, T reduced TNF- (65%, P=0.069) (Fig. 3A
) and total nitrite and nitrate (40%, P=0.1) (Fig. 3B
).
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Administration of T attenuated the partial loss of food consumption induced by inflammation and inhibited inflammation-mediated lipid peroxidation and cytotoxicity
The effect of T and T on inflammation-induced lipid peroxidation and inflammation site tissue damage was assayed by 8-isoprostane levels (17)
and by the release of LDH, respectively (11)
. Carrageenan-induced inflammation resulted in a marked increase in 8-isoprostane and LDH in the pouch. In contrast to T (33 mg/kg), T at the dose of 33 or 100 mg/kg significantly reduced 8-isoprostane (for both doses, 57%, P<0.05) (Fig. 4
A) in the pouch. At the higher dose of 100 mg/kg, T lowered LDH (30%, P=0.067) (Fig. 4B
), a marker of cytotoxicity and tissue damage. Carrageenan-induced inflammation resulted in a marked reduction in food consumption (40%, P<0.01), which is likely caused by the discomfort associated with inflammation. Administration of T at 100 mg/kg significantly attenuated (30%, P<0.03) the loss of food consumption; a smaller, nonsignificant effect was observed at the lower dose of 33 mg/kg (20%, P=0.2) (Fig. 4C
).
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Plasma and exudate concentrations of T, T, and -CEHC
To evaluate the relative bioavailability of the administrated compounds, we measured plasma and exudate concentrations of T and T as well as plasma -CEHC (Fig. 5
). Administration of T or T led to significant increases in both tocopherols in the plasma and exudate, whereas their relative increase in the exudate was more than that in the plasma. Thus, T-administrated (33 or 100 mg/kg) rats had nearly 10- or 20-fold elevation of T in exudate fluid, in contrast to 3- or 5-fold increase in the plasma compared with corn oil-fed controls (Fig. 5)
. A similar trend was observed with T. In T-administrated rats (33 or 100 mg/kg), the ratio of T to T in the exudate (0.3 or 0.7) is higher than that in the plasma (0.15), consistent with the idea that tissues may have a higher T partition than does plasma (18)
. T administration did not significantly affect T, but T caused significant decreases of T in both the plasma (55%, P<0.05) and exudate (40%, P<0.05). -CEHC, the major metabolite of T, increased in response to T supplementation. Nanomolar concentrations of -CEHC were found in the plasma, a level <10% that of plasma T. T administration caused a 2.5- to 4-fold elevation of -CEHC in the plasma (Fig. 5C
).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 15)
. Carrageenan-induced inflammation and chronic joint diseases share other features, including markedly elevated PGE2, neutrophil infiltration, cytokine formation, and tissue damage (11)
. Studies have established that in this model, COX-2, which is quickly induced in the lining macrophages and fibroblasts, is the primary enzyme responsible for the elevation of PGE2 (14)
. Thus, various COX-2 inhibitors have been shown to inhibit the formation of PGE2 in the pouch (14)
. We recently found that the major form of vitamin E in the diet, T, and its metabolite, but not T, the major form in supplements, inhibited COX-2 activity in lipopolysaccharide-activated macrophages and interlukin-1ß-treated epithelial cells (10)
. In line with this in vitro observation, the present study shows that in the carrageenan air pouch model, T (33 or 100 mg/kg), in contrast to T (33 mg/kg), significantly lowered PGE2 elevation at the site of inflammation. Local delivery of -CEHC into the air pouch also led to a significant inhibition of PGE2. These results therefore demonstrate that T and -CEHC show in vivo anti-inflammatory properties that appear to be similar to those of NSAIDs. T but not T significantly inhibits LTB4, a potent chemotactic agent that is synthesized by 5-lipoxygenase of neutrophils (8)
.
In addition to the inhibitory effects on the proinflammatory eicosanoids, in this model, T administration reduced inflammation-mediated damage, as shown by reduced lipid peroxidation and LDH activity. T attenuated the marked loss of food consumption that is likely caused by inflammation-associated discomfort. Because PGE2 is known to play a key role in causing pain and fever, a reduction of this eicosanoid may explain, in part, T’s effect on the food consumption. Besides the inhibition of COX-catalyzed reaction, other unique properties of T may contribute to the observed beneficial effects (18)
. Because of the unsubstituted 5-position compared with T, T is capable of trapping reactive nitrogen oxide, such as nitrogen dioxide (19
, 20)
and peroxynitrite (21)
, to form a stable nitrated adduct. T is better than T in protecting peroxynitrite-induced lipid peroxidation (21)
and enzyme inactivation (22)
. We recently found that in the zymosan-induced inflammation model, T supplementation consistently inhibited protein nitration and ascorbate oxidation (12)
.
At 100 mg/kg, but not 33 mg/kg, T lowered accumulation of total nitrate and nitrite (Fig. 3B
). Although some studies show that reactive nitric oxide stimulates PGE2 formation (23
, 24)
, in the current model these two events appear to be independent because T decreases PGE2 at both doses. In LPS-stimulated macrophages, we earlier found that T moderately inhibits nitrite accumulation via a moderate inhibition of the induction of inducible nitric oxide synthase (10)
. It is possible that the currently observed reduction of total nitrate and nitrite is caused by T’s suppression of this enzyme. Alternatively, T’s ability to trap reactive nitrogen oxides may also result in lowered levels of total nitrate and nitrite. However, we did not observe an apparent increase in 5-nitro--tocopherol in the exudate fluid (data not shown). Nevertheless, this possibility cannot be ruled out due to not measuring 5-nitro--CEHC, a putative breakdown product of 5-nitro--tocopherol (18)
.
In this model T appears to decrease TNF- (Fig. 3A
), a key proinflammatory cytokine known to activate macrophages and provoke the inflammatory response (25)
. Studies have shown that inhibition of TNF- provides beneficial effects on inflammatory diseases (26)
. Treatment with an antibody against TNF- has been proved to be an effective therapy for inflammatory disease (27)
. We do not know the mechanism behind T’s inhibition of TNF-.
Although T significantly inhibits the proinflammatory eicosanoids, it has no effect on neutrophil infiltration. It has been shown that in the carrageenan air pouch model, there is no casual correlation between the inhibition of PGE2 and neutrophil infiltration (11)
. For example, aspirin at doses of 100–150 mg/kg caused 50–70% reduction of PGE2, yet did not affect neutrophil infiltration (28)
. Although at higher doses (>200–300 mg/kg) aspirin inhibits cell infiltration, the mechanisms may include inhibition of NF-
B signal transduction (29)
or the activation of adenosine formation (30)
.
The relatively high bioavailability of T contributes to its in vivo inhibition of eicosanoids in the pouch. T administration resulted in a more pronounced elevation of this tocopherol in the exudate than that in the plasma (Fig. 5)
. When T showed significant inhibitory effects on PGE2 at 20 h after the injection of carrageenan, its concentration in the collected exudate was estimated to be 93.3 (33 mg/kg) to 193 nmol/g protein (100 mg/kg) (Fig. 5B
), corresponding to 10 to 20 µM, which is comparable to the apparent IC50 (5–10 µM) estimated in cell culture experiments (10)
. An increase in T administration from 33 to 100 mg/kg did not significantly improve the inhibitory potency, probably due to the saturation effect. Although when applied directly into the pouch, -CEHC significantly inhibited PGE2, the effect of T cannot be attributed to this metabolite. This is because the concentration of -CEHC is in the nanomolar range (Fig. 5C
), which is much lower than the estimated IC50 (30–40 µM) for -CEHC to inhibit COX-2 activity (10)
. Though as much as 50% of T may be converted to -CEHC (31)
, this metabolite is not likely to be accumulated in the plasma or tissues (except the kidney) because of its short retention time (16)
.
Although administration of T (33 mg/kg) led to an approximately twofold increased level in the plasma and exudate, T showed no significant effects in the present study with respect to the generation of eicosanoids and 8-isoprostane, in line with our in vitro observations (10)
. It may be relevant that T has a high baseline level in tissues as a result of the high content of T in the diet. However, administration of the same dose of T did show significant effects. This observation indicates that T possesses unique properties that are not shared T (18)
. Because T is preferentially retained by the body and is the strongest antioxidant in the vitamin E family, the possibility that supplementation of T and T (especially when T is relatively low) may result in better outcomes warrants more investigation.
The in vivo anti-inflammatory activity of T, as demonstrated by the current study, may be important for human disease prevention and therapy. 1) It may be that T can be used as a supplement for treatment of inflammatory diseases to decrease proinflammatory eicosanoids and damage from inflammation. Not only does T reduce PGE2, it inhibits lipoxygenase-catalyzed synthesis of LTB4 and decreases TNF-, an activity most NSAIDs do not have (28)
. These findings suggest a potentially superior pharmaceutical use for T compared with traditional NSAIDs. 2) T may be useful in cancer prevention. It is known that COX-2 and PGE2 are elevated in inflammation-associated diseases, including cancer (32)
. Frequent intake of NSAIDs such as aspirin is known to reduce the risk of certain cancers (33
, 34)
. Recently, Helzlsouer et al. (35)
reported that in a nested case control study, men in the highest quintile of plasma T levels had a fivefold reduction in the risk of prostate cancer compared with those in the lowest quintile. We recently found that T but not T showed antiproliferative effects on prostate and lung cancer cell lines, but had no effect on normal epithelial cells (Q. Jiang, unpublished observation). 3) The anti-inflammatory effects of T may be beneficial in cardiovascular disease, another inflammation-associated disorder (36)
. Several studies (37
, 38)
reported that plasma concentrations of T, but not T, are inversely associated with the incidence of coronary heart diseases. Frequent intake of nuts, a rich source of T, is associated with reduced risk for cardiovascular disease (39)
.
In conclusion, T inhibits the proinflammatory eicosanoids, suppresses proinflammatory cytokine, and attenuates inflammation-mediated damage in a rat inflammation model. The current observations together with the cited studies strongly suggest that T, the most abundant form of vitamin E in the U.S. diet, is important to human health and deserves more attention.
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ACKNOWLEDGMENTS |
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Received for publication October 9, 2002. Accepted for publication January 10, 2003.
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REFERENCES |
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