774 Note Biol. Pharm. Bull. 34(5) 774—778 (2011) Vol. 34, No.

Evaluation of the Cyclooxygenase Inhibiting Effects of Six Major

Cannabinoids Isolated from Cannabis sativa
Lucia Renee RUHAAK,*, a,b,† Jenny FELTH,a,# Pernilla Christina KARLSSON,c Joseph James RAFTER,c
Robert VERPOORTE,b and Lars BOHLINa
a
Division of Pharmacognosy, Department of Medicinal Chemistry, Biomedical Centre, Uppsala University; Box 574, SE-
751 23 Uppsala, Sweden: b Division of Pharmacognosy, Section Metabolomics, Institute of Biology, Leiden University;
2300 RA, Leiden, the Netherlands: and c Department of Biosciences and Nutrition, Karolinska Institutet; Novum, S-141 86
Huddinge, Sweden. Received December 22, 2010; accepted February 19, 2011; published online February 28, 2011

Cyclooxygenase enzymes (COX-1 and COX-2) catalyse the production of prostaglandins from arachidonic
acid. Prostaglandins are important mediators in the inflammatory process and their production can be reduced
by COX-inhibitors. Endocannabinoids, endogenous analogues of the plant derived cannabinoids, occur normally
in the human body. The Endocannabinoids are structurally similar to arachidonic acid and have been suggested
to interfere with the inflammatory process. They have also been shown to inhibit cancer cell proliferation. Anti-
inflammatory effects of cannabinoids and endocannabinoids have been observed, however the mode of action is
not yet clarified. Anti-inflammatory activity (i.e., inhibition of COX-2) is proposed to play an important role in
the development of colon cancer, which makes this subject interesting to study further. In the present work, the
six cannabinoids tetrahydrocannabinol (D D 9-THC), tetrahydrocannabinolic acid (D D 9-THC-A), cannabidiol (CBD),
cannabidiolic acid (CBDA), cannabigerol (CBG) and cannabigerolic acid (CBGA), isolated from Cannabis sativa,
were evaluated for their effects on prostaglandin production. For this purpose an in vitro enzyme based COX-
1/COX-2 inhibition assay and a cell based prostaglandin production radioimmunoassay were used. Cannabinoids
inhibited cyclooxygenase enzyme activity with IC50 values ranging from 1.7 · 103 to 2.0 · 104 M.
Key words cannabinoid; cyclooxygenase inhibition; prostaglandin production

Cyclooxygenase enzymes (COX enzymes) catalyse the chain in cannabinoids is present in the endocannabinoids as
production of prostaglandins, which are important mediators the last five carbons of the fatty acid chain, and the C-3 OH
in the inflammatory process. To date, two isoforms of COX might correspond to the polar hydroxyl end of the endo-
have been identified; a constitutively expressed enzyme, cannabinoids. Furthermore, the relative distances between
COX-1 and an inducible enzyme, COX-2,1,2) of which the lat-
ter is induced by inflammatory stimuli. An important group
of anti-inflammatory drugs is the Non-Steroid Anti Inflam-
matory Drugs (NSAIDs), of which aspirin and indomethacin
are representatives. These compounds act by inhibiting the
COX enzymes. The substrate for the prostaglandin produc-
tion is arachidonic acid (Fig. 1),1) an eicosanoid, which is
produced on demand by phospholipase A2 from arachido-
nate, which is stored in the lipid bilayers of the cell wall.3) In
recent years, COX-2 overexpression has been associated with
colon cancer development, and COX enzyme inhibition is
studied as a potential target for cancer chemoprevention.4,5)
Other compounds in the eicosanoid group are the endo-
cannabinoids. These endogenous compounds bind to cellular
receptors, including the cannabinoid receptors, which are the
molecular targets of the active principle in Cannabis sativa.
The biological function of the endocannabinoids involves
several regulatory agents, forming the endocannabinoid sys-
tem (ECS).6) It has been reported that endocannabinoids also
can function as substrates for the COX enzymes resulting in
production of prostaglandin ethanolamides and prostaglandin
glycerol esters.7,8) Recently, the endogenous cannabinoid
anandamide was shown to induce COX-2 dependent cell
death in colon cancer cells.9)
There are several structural (Fig. 1) and physiological sim-
ilarities between human endocannabinoids and cannabinoids
occurring in plant material. Structurally the 5-carbon side
Fig. 1. Structural Formulas of the Endocannabinoid Anandamide (1) and
the Endocannabinoid Precursor Arachidonic Acid (2) together with the Six
†
Present address: Department of Chemistry, University of California at Davis, Cannabinoids; D 9-THC (3), D 9-THCA-A (4), CBD (5), CBDA (6), CBG (7),
Davis, CA 95616, U.S.A. CBGA (8)

∗ To whom correspondence should be addressed. e-mail: Lruhaak@ucdavis.edu © 2011 Pharmaceutical Society of Japan
#
Equal contribution with the first author.
May 2011 775

the groups are comparable due to the ring system in cannabi- becco’s modified Eagle’s medium (DMEM)-high glucose and
noids, which can be mimicked by the U-shaped endocannabi- trypsin-ethylenediaminetetraacetic acid (EDTA) were ob-
noids and their four double bonds.10) Also physiologically tained from Invitrogen, Taastrup, Denmark.
there are similarities, since both cannabinoids and endo- Cell Culture The human colon adenocarcinoma cell line
cannabinoids bind to the cannabinoid receptors.11) Endo- HT29, was cultured in monolayer in DMEM (Dulbecco’s
cannabinoids, such as anandamide, are derived from arachi- modified Eagle medium supplemented with 10% fetal bovine
donic acid and are structurally similar to this compound (Fig. serum (FBS), 2 mM L-glutamine, and 1% penicillin/strepto-
1). mycin) at 37 °C and 5% CO2. All experiments were per-
Altogether, these similarities gave rise to the hypothesis formed with 60—80% confluent cells and 0.1% DMEM
that cannabinoids can affect the COX enzyme activity. (0.1% FBS). Pure compounds were dissolved in ethanol and
Several studies have demonstrated anti-inflammatory activi- diluted in 0.1% DMEM (with the final concentration in the
ties in vivo and in vitro for various cannabinoid com- cell cultures being maximum 0.25% ethanol).
pounds,12—18) which makes this hypothesis very plausible. In- Enzyme-Based Inhibition Assay The assay followed
hibiting effects on COX enzyme activity have also previously the original method described by White and Glassman,25)
been observed for cannabidiol and cannabidiolic acid,17,19) with modifications as described by Noreen et al.26) The assay
and cannabinoids have potential to affect the potency of described below was used for both COX-1 and COX-2 en-
NSAIDs.20,21) Furthermore, in recent years, it has been shown zymes. In short, 20 m l of each sample was dispensed in a 96-
that the ECS can protect against colonic inflammation,6,22) well plate. All samples were dissolved in 20% dimethyl sul-
which is of interest in prevention of bowel disease and colo- foxide (DMSO) in TRIS buffer. To determine minimal and
rectal cancer. The cannabinoid receptors are suggested to be maximal activity of the enzyme, 20% DMSO in TRIS buffer
involved in the control of colonic inflammation,6,22) however, was used as the sample. Total inhibition of the enzyme in the
the mode of action for the anti-inflammatory effects of minimum wells was reached by addition of 10 m l of 2 M HCl
cannabinoids is not yet clarified. to the wells before the enzyme was added. Cofactors were
In the present study we evaluated the COX-mediated anti- dissolved in TRIS buffer to concentrations of 1.27 mg/ml
inflammatory properties of six different naturally occuring hematin, 6.50 mg/ml adrenalin and 1.50 mg/ml gluthatione,
cannabinoids; tetrahydrocannabinol (D 9-THC), tetrahydro- giving final concentrations in the wells of 1.3 m g/ml, 1.3
cannabinolic acid-A (THCA-A), cannabidiol (CBD), canna- mg/ml and 0.3 mg/ml respectively. COX enzyme was mixed
bidiolic acid (CBDA), cannabigerol (CBG) and cannabigero- with the co-factors, pre-incubated and activated on ice for
lic acid (CBGA) (Fig. 1). An enzyme-based in vitro COX 5 min. Sixty microliters of enzyme-cofactor solution was
inhibition assay was used to evaluate the effects on both added to the sample in the wells, and the plate was incubated
COX-1 and COX-2 on enzyme-level, while a cell-based for 10 min on ice. The activity of the enzyme in the wells was
prostaglandin production assay was used to evaluate the 6U (COX-1) or 3U (COX-2). Twenty microliters of 14C-
effects on COX-2 at cellular level. arachidonic acid (14C-AA) solution was dispensed in each
well and to start the enzymatic reaction, the plate was incu-
MATERIALS AND METHODS bated in a 37 °C waterbath for 15 min (COX-1) or 3 min
(COX-2). The reaction was stopped by addition of 10 m l
Materials All solvents were purchased from Lab-Scan, of HCl (2 M). To separate the non-converted 14C-AA from
Dublin, Ireland, and were of analytical grade. Scientific sam- the 14C-labeled prostaglandins, column chromatography
ples of cannabinoids (D 9-THC, THCA-A, CBD, CBDA, (Silica gel 60, particle size 0.063—2 mm) was used. The
CBG and CBGA) were provided by Prof. Robert Verpoorte columns were equilibrated using 2 ml of eluent, consisting of
and Dr. Arno Hazekamp, Leiden University, The Nether- heptane : ethyl acetate : acetic acid (70 : 30 : 1), thereafter the
lands. The cannabinoids were isolated from Cannabis sativa samples were applied, and the non-converted AA was eluted
and characterized and quantified using the chromatography using 4 ml of the same eluent. The prostaglandins were
and 1H-NMR methods as described by Hazekamp et al.23,24) then eluted using 3 ml of a second eluent, consisting of
All cannabinoid samples were at least 92% pure. dioxane : methanol (85 : 15). Scintillation fluid was added
COX-1 enzyme, purified from ram seminal vesicles and to the samples, and the amount of radioactively labeled
COX-2 enzyme, purified from sheep placental cotyledons, prostaglandin in the samples was determined using a Packard
and the reference compound NS-398 (N-[2-(cyclo-hexyl- scintillation spectrometer. Percent inhibition values were cal-
oxy)-4-nitrophenyl]methanesulphonamide) were purchased culated and IC50-values were obtained by applying the non-
from Cayman Chemical Co., Ann Arbor, MI, U.S.A. linear regression analysis tool of Graph Pad Prism (Graph-
Hematin was obtained from ICN biomedicals Inc., Aurora, Pad Software Inc., CA, U.S.A.).
Ohio, U.S.A. Adrenalin was purchased from Apoteket AB, Prostaglandin E2 (PGE2) Production in HT29 Cells
Göteborg, Sweden. Reduced gluthatione, indomethacine, un- PGE2 is a major product produced by COX from arachidonic
labeled arachidonic acid, anti-prostaglandin E2, prostaglandin acid and is often used to estimate COX activity in cells. The
E2 standard, Bovine Serum Albumin, tumor necrosis factor method used is a standard procedure for measuring PGE2
(TNF)-a and charcoal were obtained from Sigma-Aldrich, production in cells, and has previously been described in de-
St. Louis, MO, U.S.A. 14C-Arachidonic acid, [5,6,8,11,12,- tail.27—29) In brief, HT29 cells were seeded out at a concen-
14,15(n)-3H] Prostaglandin E2 and dextran molecular weight tration of 3.30105 cells/well. At day 2, 100 m M aspirin was
(mw) 70000 was purchased from Amersham Pharmacia, added to the wells to prevent activation of COX-1. At day 3,
Stockholm, Sweden, while silica gel 60, particle size 0.063— the cells were incubated with TNF-a (50 ng/ml) and cannabi-
2 mm was obtained from Merck, Darmstadt, Germany. Dul- noid samples (12.5 or 25 m M) for 5 h, thereafter the test solu-
776 Vol. 34, No. 5

tion was replaced with medium containing 100 m mol/l presented by concentration–effect graphs (Fig. 3A). The
arachidonic acid (Sigma) and the cells were incubated for 1h. IC50-values are presented in Table 1. The IC50-value of the
The concentration of released prostaglandin E2 (PGE2) was reference compound indomethacin was within acceptable
quantified using radio immuno-assay (RIA), according to the limits of the value reported previously for this COX-1 assay
protocol supplied by Sigma Chemical Co., using [3H]PGE2 (1.4 · 106 M),26) confirming that the assay was successful.
and polyclonal antiserum to PGE2 (Sigma). The amount of When screened for COX-2 enzyme inhibiting activity D 9-
prostaglandins in each sample was detected using a scintilla- THCA-A, CBG and CBGA showed more than 30% inhibi-
tion counter, and expressed as the percentage inhibition of tion. Interestingly, CBDA, which was recently reported to se-
the TNF-a treated cells. Each cannabinoid was tested at least lectively inhibit COX-2,19) did not reach the 30% inhibition
twice in the cell system and later analyzed in duplicate in the threshold (Fig. 2), and was therefore not considered in our
RIA. The results were expressed as the percentage inhibition further COX-2 inhibition studies. The inhibition of D 9-
of the TNF-a treated cells. In all experiments untreated cells THCA-A, CBG and CBGA was measured at concentrations
were included as controls, and the selective COX-2 inhibitor ranging from 3.18 · 103 to 2.78 · 105 M, as represented by
NS398 was used as a reference compound for comparison of the concentration–effect graphs (Fig. 3B) with IC50-values
inhibiting activity. presented in Table 1. The IC50 value of the reference com-
Prior to the PGE2 experiments, all cannabinoid samples pound indomethacin was within acceptable limits of the
were tested for cytotoxicity in the AlamarBlueTM assay to en- value previously reported for this COX-2 assay (1.64 · 106
26)
sure that potential COX-2 inhibitory effects were not due to M), confirming that the assay results were reliable.
cell death.30,31) A cell survival of approximately 70% was Complementary to the enzyme-inhibition assay, the effects
considered as acceptable for studying the prostaglandin pro-
duction. Cannabinoid concentrations causing cell death (i.e.,
cell survival 70%) were excluded from the PGE2 produc-
tion experiments.

RESULTS

Enzyme-Based Inhibition Assay The inhibitory effects

of six cannabinoids on the cyclooxygenase enzyme activity
was evaluated by an in vitro COX enzyme inhibition assay.
D 9-THC, D 9-THCA-A, CBD, CBDA, CBG and CBGA were
screened for their ability to inhibit COX-1 and COX-2 at a
concentration of 100 mg/ml (approximately 3 · 104 M), since
higher concentrations were assumed to be irrelevant. In this
screening, an enzyme inhibition of 30% was considered as
sufficient to be relevant, and was set as a cutoff limit for
compounds to investigate further. D 9-THCA-A, CBDA, CBG
and CBGA showed more than 30% inhibition on COX-1
(Fig. 2). The concentration-dependent activity (i.e. inhibition
of COX-1) for these compounds was further evaluated at
concentrations ranging from 3.18 · 103 to 2.78 · 105 M, as

Fig. 3. (A) Graphs Representing the COX-1 Inhibition of D 9-THCA-A,

CBDA, CBGA and Indomethacin in the Enzyme Based Assay
For each datapoint n3.
(B) Graphs Representing the COX-2 Inhibiton of D 9-THCA-A, CBG,
CBGA and Indomethacin in the Enzyme Based Assay
For each datapoint n3.

Table 1. COX Inhibition IC50-Values Determined for D 9-THCA-A, CBG,

CBGA and Indomethacin Using an Enzyme Based in Vitro Assay

IC50 (M)
Compound
COX-1 COX-2

D 9-THCA-A 1.7 · 103 6.3 · 104

CBDA 4.7 · 104 N.D.a)
Fig. 2. Screening of Six Cannabinoids for Their Potential to Inhibit COX- CBG N.D.a) 2.7 · 104
1 and COX-2 Enzymes CBGA 4.6 · 104 2.0 · 104
All cannabinoids were screened at concentrations of 100 m g/ml. To justify further Indomethacin 3.1 · 106 9.3 · 105
analysis, a cut off value of at least 30% inhibition was used, represented by the black
dotted line. a) N.D., not determined.
May 2011 777

the cannabinoids showed high COX selectivity except from

CBDA, which only inhibited COX-1. This finding is contra-
dictory to previously reported results by Takeda et al., where
CBDA was found to be a selective COX-2 inhibitor in an en-
zyme inhibition assay using purified COX enzymes.19) These
inconsistencies might be caused by differences in the detec-
tion method. In the present study radioactively labeled
prostaglandin was measured, while Takeda et al. measured
the oxidation of TMPD spectrophotometrically. Alternatively,
as the cannabinoids used in the studies were purified from
plant material, different impurities in the samples could
cause different results. Further studies, preferably in human
cell lines, are needed to validate the COX inhibition by
cannabinoids.
Fig. 4. Decrease in Prostaglandin Production in TNF-a Stimulated HT29 In the screening, it was observed that D 9-THC showed
Cells stimulation in a dose-related matter (between 3.18 · 104 and
The prostaglandin production inhibitor NS398 was used as a reference compound.
Error bars represent S.D.
3.18 · 105 M) both in the COX-1 inhibition assay and the
COX-2 inhibition assay (data not shown). However, the
COX-inhibition assay is not designed to quantify COX
of cannabinoids on prostaglandin production were examined enzyme activation, and hence no definitive conclusions can
in a cell based assay. Six different cannabinoids were tested be drawn from these findings.
for their ability to decrease prostaglandin production in TNF- Interestingly, CBD and D 9-THC showed low activity in the
a stimulated HT29 cells. Prior to measuring the prosta- in vitro assay of the COX-enzymes in comparison with the
glandin production, the effects of cannabinoids on cell sur- other cannabinoids tested. The COX inhibition assay is an in
vival were investigated, to make sure that the effects were not vitro assay where purified COX enzyme (from ram seminal
due to cell death. A cell survival of approximately 70% was vesicles and sheep placental cotyledons, respectively) is
considered as acceptable for studying the prostaglandin pro- used. This assay is far from the human in vivo conditions.
duction, and the observed effects on the PGE2 production are Therefore, we complementarily used human colon cancer
very unlikely to be explained by cell death. Both apoptosis cells to investigate if the prostaglandin production would be
and necrosis make the cells detach from the plate surface. No inhibited also in living cells. The inhibition of prostaglandin
such signs were observed. D 9-THC, CBD, CBDA and CBG production in cancer cells is of great interest, since the in-
were tested at concentrations of 2.5 · 105 M, whereas D 9- flammatory process is believed to be of importance for colon
THCA-A and CBGA were tested at a concentration of carcinogenesis.33) As shown in Fig. 4, the results (e.g. inhibi-
6.25 · 105 M. However, higher concentrations of cannabi- tion of PGE2 production) from the cell-based assay were sim-
noids caused a high cytotoxicity and could not be used in the ilar for all cannabinoids. All compounds tested inhibited the
experiments. The results, as presented in Fig. 4, showed that production of PGE2 only slightly. An experiment with higher
D 9-THC, D 9-THCA-A, CBD, CBG and CBGA inhibited concentrations might give more clear results. However,
prostaglandin production, however the level of inhibition was higher concentrations of the cannabinoids were cytotoxic,
low (10%). CBDA, on the other hand seemed to stimulate causing detachment of cells and signs of cell death, and such
the prostaglandin production (Fig. 4). experiments were not possible to perform using this cell-
based assay.
DISCUSSION The cannabinoids are known to be involved in the immune
system via the CB2 receptor. The binding constants Ki for
Cannabinoids have been shown to possess anti-inflamma- D 9-THC interacting with the CB1 and CB2 receptors are
tory effects,12—18) but the mechanism of action is not yet 8.0 · 105 M and 3.2 · 105 M respectively.34) These binding
known. COX enzyme inhibiting activity has previously been constants are in the same range as the IC50 values we found
observed for CBD and CBDA.17,19) Overexpression of COX- for the COX-inhibition by cannabinoids. This might indicate
2 has in recent years also been associated with colon cancer a possibility of physiologically important effects of the COX-
development,5) and COX-2 enzyme inhibition is regarded as inhibiting cannabinoids via interaction with the COX-en-
a potential target for cancer chemoprevention.4) Interestingly, zymes. Further in vitro studies are required to prove such ef-
endocannabinoid levels are elevated in colon cancer tissue, fects, but the present study shows that several of the major
and they also inhibit cancer cell proliferation by acting at cannabinoids may also affect other receptors than CB1 and
cannabinoid receptors.32) Recently, it has also been shown CB2. Interestingly, a recent report, linking COX-2 inhibition
that the ECS can protect against colonic inflammation,6,22) to increased endocannabinoid levels, suggests the ECS and
which is of interest in prevention of bowel disease and col- the COX-mediated prostaglandin pathway to be closely con-
orectal cancer. Additionally, cannabinoids have been shown nected.35)
to affect the potency of NSAIDs,20,21) potentially via modula- In conclusion, it is clear that cannabinoids inhibit COX-
tion of the COX pathway. enzymes, but in a higher concentration range, as compared
In the present study, six major cannabinoids isolated from to anti-inflammatory drugs (i.e. indomethacin). The obvious
plant material modulated the activity of COX enzymes, with contradiction regarding the selectivity for CBDA, as com-
IC50 values ranging from 1.7 · 103 to 2.0 · 104 M. None of pared to the previous report by Takeda et al.,19) is interesting
778 Vol. 34, No. 5

and should be object for further investigation. Additional 14) Sofia R. D., Nalepa S. D., Harakal J. J., Vassar H. B., J. Pharmacol.
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