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Vol. 28, Issue 11, 1291-1296, November 2000
8-tetrahydrocannabinol to
7-Oxo-8-tetrahydrocannabinol in Human Liver Microsomes
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University (T.M., N.K., S.H., K.W., I.Y.), Hokuriku, Japan; and Department of Legal Medicine, Kanazawa University Faculty of Medicine, School of Medicine, Kanazawa, Japan (T.O.)
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Abstract |
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 Top
 Abstract
 Introduction
Experimental Procedures
Results
Discussion
References
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The human liver enzyme microsomal alcohol oxygenase was able
to oxidize both 7
- and
7
-hydroxy-
8-tetrahydrocannabinol (7- and
7-hydroxy-8-THC) to 7-oxo-8-THC. The
oxidative activity was determined by using a panel of 12 individual
cDNA-expressed human cytochrome P450s (CYPs) (1A1, 1A2, 2A6, 2B6, 2C8,
2C9-Arg, 2C9-Cys, 2C19, 2D6-Met, 2D6-Val, 2E1 and 3A4). Among the CYP
isoforms examined, CYP3A4 showed the highest activity for both of
substrates. The metabolism of 7- and
7-hydroxy-8-THC to 7-oxo-8-THC was
also detected for CYPs 1A1 (4.8% of CYP3A4), 1A2 (4.7%), 2A6 (2.3%),
2C8 (16.6%), and 2C9-Cys (5.4%), and CYPs 1A1 (0.4%), 2C8 (1.3%),
2C9-Arg (4.3%), and 2C9-Cys (0.9%), respectively. The 7- and
7-hydroxy-8-THC microsomal alcohol oxygenase
activities in human liver were significantly inhibited by addition of
100 µM troleandomycin, 1 µM ketoconazole, and anti-CYP3A antibody,
although these activities were not inhibited by 1 µM 7,8-benzoflavone
and 50 µM sulfaphenazole. When the substrates were incubated with the
CYP3A4-expressed microsomes under oxygen-18 gas phase, atmospheric
oxygen was incorporated into 35% of 7-oxo-8-THC formed
from 7-OH-8-THC, but only 12% of
7-oxo-8-THC formed from 7-OH-8-THC.
These results indicate that CYP3A4 is a major isoform responsible for
the oxidation of 7- and 7-hydroxy-8-THC to
7-oxo-8-THC in liver microsomes of humans, although the
oxidation mechanisms for 7- and 7-hydroxy-8-THC
might be different.
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Introduction |
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Top
Abstract
Introduction
Experimental Procedures
Results
Discussion
References
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Tetrahydrocannabinol (THC)1
, a
psychotropic component of Cannabis sativa L. (marijuana), is
mainly hydroxylated at allylic position at C-7 (for
8-THC), C-8 (for
9-THC), and C-11 (both of
8- and 9-THC)
together with oxidation at the pentyl side chain in various animals,
including humans (Harvey and Paton, 1986
). At present, over 80 metabolites have been identified from THC (Harvey and Paton, 1986).
Cytochrome P450 (CYP) has been suggested to play a major role in the
oxidation of THC in humans (Halldin et al., 1982; Yamamoto et al.,
1983, 1984). The metabolic reaction is complicated and the isoforms
responsible for particular metabolic reaction have not been completely
elucidated. In some cases, the effects of metabolites are greater than
those of THC (Yamamoto and Yoshimura, 1982; Yamamoto, 1986) and these
metabolites have been suggested to contribute to the psychoactivity of
the parent compound.
The content of 8-THC in marijuana of Mexican
origin is 10% of the total THC (Hively et al., 1966), but it is
possible that it is actually formed by isomerization (Turner et al.,
1980). There have been many reports concerning metabolism of
8-THC because it shows comparable
pharmacological activity to 9-THC and is
chemically more stable. Furthermore, 8-THC and
its derivatives have been used for the study of medicinal chemistry and
pharmacology (Mechoulam et al., 1999; Waser and Martin, 1999; Zurier et
al., 1999). We have shown that 7-oxo-8-THC
formed from 7-hydroxy-8-THC is one of the
active metabolites (Narimatsu et al., 1984). Bornheim et al. (1992)
have reported that antibody raised against mouse hepatic CYP3A
inhibited the formation of most of the
8-hydroxy-9-THC and
8-oxo-9-THC formation from
9-THC by human liver microsomes. However, the
contribution of the human CYP3A isoform to the formation of
8-oxo-9-THC has not been directly
demonstrated. 9-THC, not
8-hydroxy-9-THC, was used for substrate
although 8-oxo-9-THC was biotransformed from
8-hydroxylated metabolites by further enzymatic oxidation. Its is well
known that secondary alcohols such as hydroxysteroids and xenobiotics
are oxidized to the corresponding ketones by dehydrogenases in
microsomes and cytosol (Maser and Bannenberg, 1994; Furster et al.,
1996; Yamano et al., 1997). We have found, however, that the
7-oxo-8-THC was biotransformed from 7- and
7-hydroxy-8-THC by the liver microsomal
enzyme microsomal alcohol oxygenase (MALCO) (Narimatsu et al., 1988).
We have recently purified two CYP isoforms, named P450GPF-B and P450
MDX-B, that are the major enzymes responsible for the formation of
7-oxo-8-THC in liver microsomes of guinea pig
(Matsunaga et al., 1997) and mouse (Matsunaga et al., 1998),
respectively. These enzymes are estimated to be CYP3A isoforms from
NH2-terminal amino acid sequences and catalytic
properties. Interestingly, in the reconstituted system of P450GPF-B,
oxygen-18 (18O) derived from atmospheric oxygen
was incorporated into 7-oxo-8-THC formed from
7-OH-8-THC, whereas incorporation of the
stable isotope into the oxidized metabolites from
7-OH-8-THC was negligible (Matsunaga et
al., 1997). To our knowledge, no detailed study has been reported with
respect to the specific isoform(s) involved in the formation of
7-oxo-8-THC from 7- and
7-hydroxy-8-THC in humans. However,
purification of the major enzymes responsible for the MALCO activity
from human liver may be difficult. More than 15 human CYP gene products
have been identified, and several forms play important roles in
xenobiotic metabolism (Kerremans, 1996; Nelson et al., 1996). Recently,
a number of approaches using the inhibitors and the recombinant human
CYPs have been developed for the identification of human CYPs
responsible for the metabolism of particular xenobiotics in vitro
(Birkett et al., 1993; Zhao et al., 1996; Nakamura et al., 1998).
In the present study, we identify the human CYP isoform involved in the
7-oxo-8-THC formation by human liver
microsomes and then with the use of 12 different recombinant human
CYPs, including two allelic variants. Furthermore, we characterize the
oxidation mechanisms for 7- and
7-hydroxy-8-THC by using stable isotope of
oxygen molecules.
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Experimental Procedures |
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Top
Abstract
Introduction
Experimental Procedures
Results
Discussion
References
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Materials.
7- and 7-Hydroxy-8-THC (Mechoulam et
al., 1972), 7-oxo-8-THC (Narimatsu et al.,
1984), and 5'-nor-8-THC-4'-oic acid (Ohlsson
et al., 1979) were prepared by the methods previously reported.
Purities of the cannabinoids were checked to be more than 98% by gas
chromatography (GC). Troleandomycin and sulfaphenazole were purchased
from Sigma Chemical Co. (St. Louis, MO); 7,8-benzoflavone was from Wako
Pure Chemicals (Osaka, Japan); and ketoconazole was from Daiichi Pure
Chemicals (Tokyo, Japan). The human CYPs [1A1, 1A2, 2A6, 2B6, 2C8,
2C9-Arg144 (2C9-Arg),
2C9-Cys144 (2C9-Cys), 2C19,
2D6-Met374 (2D6-Met),
2D6-Val374 (2D6-Val), 2E1, and 3A4] containing
microsomes prepared from human B-lymphoblastoid cells expressed cDNA
together with control microsomes (with or without vector) were
purchased from Gentest Corporation (Woburn, MA). Other chemicals and
solvents used were of the highest quality commercially available.
Tissue Samples and Preparation of Microsomes.
Human liver samples were obtained from a 57-year-old woman (HL11) and
16-year-old man (HL12) who were killed in traffic accidents. The use of
the human liver for these studies was approved by Ethics Committee of
Kanazawa University, Faculty of Medicine. Microsomes from the human
livers were prepared by the method reported previously (Matsunaga et
al., 1996) and were stored at 
80°C until use.
Measurement of MALCO Activity.
The formation of 7-oxo-8-THC was measured
essentially as previously described (Matsunaga et al., 1997).
7-Hydroxy-8-THC (72.7 µM) was incubated with
human liver microsomes (0.2-0.3 mg protein) or human B-lymphoblastoid
cell microsomes (0.5 mg of protein), an NADPH-generating system (0.5 mM
NADP, 10 mM glucose 6-phosphate, 1 unit of glucose 6-phosphate
dehydrogenase, 10 mM magnesium chloride) and 100 mM potassium phosphate
buffer (pH 7.4) to make a final volume of 0.25 ml. The mixture was
incubated at 37°C for 20 min. 7-Oxo-8-THC
was produced linearly for 30 min in this system. Metabolites were
extracted with 2.5 ml of ethyl acetate after addition of 5'-nor-8-THC-4'-oic acid as an internal
standard (5 µg) and a portion of the extract was evaporated to
dryness. 7-Oxo-8-THC formed was analyzed by
electron capture detector-GC after derivatization to
heptafluorobutyrate or by gas chromatography/mass spectrometry (GC/MS)
after conversion to the trimethylsilyl derivative as described
previously (Matsunaga et al., 1997).
- and
7-hydroxy-8-THC (72.7 µM), and
sulfaphenazole (50 µM), 7,8-benzoflavone (1 µM), ketoconazole (1 µM), or troleandomycin (100 µM). All inhibitors were dissolved in
methanol and added to the incubation mixture at a final methanol
concentration of 2%. Previous studies have shown that the primary
mechanism of troleandomycin inhibition of human CYP is
metabolite-intermediate complexation (Pessayre et al., 1982; Watkins et
al., 1985; Lindstrom et al., 1993). Therefore, incubation mixture
containing troleandomycin was preincubated in the presence of the
NADPH-generating system at 37°C for 20 min and the reaction initiated
by addition of substrate and a further aliquot of NADPH-generating
system. All other incubation mixtures contained substrate and
inhibitors were initiated the reaction by addition of the
NADPH-generating system without preincubation. The assays were
performed as described above.
For immunoinhibition studies, the IgG fraction was prepared from
antiserum against P450 MDX-B as previously reported (Matsunaga et al.,
1998). The antibody did not cross-react with CYP-expressed microsomes
except CYP3A4 used in the present study (data not shown). The antibody
was added to medium containing microsomes and 100 mM potassium
phosphate buffer (pH 7.4) and preincubated at 37°C for 30 min. The
substrate was added to the medium, and the reaction was started by
adding an NADPH-generating system as described above. After incubation
at 37°C for 20 min, the metabolite was assayed by the same methods
described above using electron capture detector-GC.
To examine oxygen incorporation from atmospheric molecular oxygen into
7-oxo-8-THC,
7-hydroxy-8-THC was incubated with
CYP3A4-containing microsomes prepared from human B-lymphoblastoid cells
that coexpressed cytochrome b5 and with
NADPH-CYP reductase at 37°C for 20 min under
18O2. After incubation, the
metabolites extracted with ethyl acetate were converted to
trimethylsilyl derivatives and analyzed by the same methods described
above using GC/MS.
Other Methods.
Protein concentration was estimated by the method of Lowry et al.
(1951), using bovine serum albumin as a standard. CYP contents in human
liver microsomes were determined by the methods of Omura and Sato
(1964).
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Results |
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Top
Abstract
Introduction
Experimental Procedures
Results
Discussion
References
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Metabolism of 7-Hydroxy-8-THC by Human Liver
Microsomes and CYPs Expressed in Microsomes of Human B-Lymphoblastoid
Cells.
7- and 7-Hydroxy-8-THC MALCO activities
in human livers were 0.13 to 0.22 and 0.62 to 0.79 nmol/min/nmol P450,
respectively (Fig. 1). The formation of
7-oxo-8-THC from
7-hydroxy-8-THC was severalfold higher than
that from 7-hydroxy-8-THC. The metabolism
of 7- and 7-hydroxy-8-THC to
7-oxo-8-THC by human CYPs was examined in
human B-lymphoblastoid cell microsomes containing cDNA-expressed CYPs
1A1, 1A2, 2A6, 2B6, 2C8, 2C9-Arg, 2C9-Cys, 2C19, 2D6-Met, 2D6-Val, 2E1,
and 3A4 (Fig. 1). Among the human CYPs examined, CYP3A4 showed the
highest activity for both of the substrates. The activities for 7-
and 7-hydroxy-8-THC were 2.07 and 6.98 nmol/min/nmol P450, respectively. The metabolism of
7-hydroxy-8-THC to
7-oxo-8-THC by CYPs 1A1, 1A2, 2A6, 2C8, and
2C9-Cys were 4.8, 4.7, 2.3, 16.6, and 5.4%, respectively, of the rate
of metabolism by CYP3A4. The metabolism of
7-hydroxy-8-THC to
7-oxo-8-THC by CYPs 1A1, 2C8, 2C9-Arg, and
2C9-Cys were only 0.4, 1.3, 4.3, and 0.9%, respectively, of the rate
of metabolism by CYP3A4. None of the other cDNA-expressed human CYP
isoforms together with microsomes from control cells (with or without
vector) metabolized 7-hydroxy-8-THC to
7-oxo-8-THC to any significant extent.
|
Effects of Chemical Inhibitors and Anti-CYP3A Antibody on
7-Hydroxy-8-THC MALCO Activity.
7,8-Benzoflavone, sulfaphenazole, and troleandomycin are selective
inhibitors of human CYP1A, CYP2C (except CYP2C19), and CYP3A
subfamilies, respectively (Ono et al., 1996). Ketoconazole is also a
selective inhibitor of human CYP3A isoforms at concentration 1 µM
(Baldwin et al., 1995), although ketoconazole inhibited the activities
of the other CYPs at higher concentration (Newton et al., 1995). The
formation of 7-oxo-8-THC from 7- and
7-hydroxy-8-THC was inhibited by 88 and
84%, respectively, when troleandomycin (100 µM) was preincubated
with human liver microsomes in the presence of an NADPH-generating
system before assaying for the substrate oxidation (Fig.
2). Ketoconazole also inhibited
7- and 7-hydroxy-8-THC MALCO activities
by 83 and 69%, respectively, of control values at 1 µM
concentrations. However, 7,8-benzoflavone (1 µM) and sulfaphenazole
(50 µM) failed to inhibit the activity (Fig. 2).
|
- and 7-hydroxy-8-THC MALCO activities
in human liver. When the antibody was added 3-fold of microsomal
protein, 7- and 7-hydroxy-8-THC MALCO
activities were inhibited to 29 and 25%, respectively, of the control
value (Fig. 3).
|
Incorporation of Atmospheric Oxygen into
7-Oxo-8-THC.
7- and 7-Hydroxy-8-THC were incubated
with CYP3A4-expressed microsomes under
18O2 and the trimethylsilyl
derivative of metabolites was analyzed by GC/MS. The relative
intensities of molecular ions at m/z 400 and 402 are shown in Table 1. The ratio in
relative intensities of ions at m/z 402 to 400 of
7-oxo-8-THC formed from
7-hydroxy-8-THC was 0.63, showing that
18O derived from atmospheric oxygen molecule was
incorporated into 35% of the oxidized metabolite. In the case of
7-hydroxy-8-THC, the ratio was 0.24 and
18O was incorporated into 12% of the metabolite.
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Discussion |
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Top
Abstract
Introduction
Experimental Procedures
Results
Discussion
References
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8-THC is biotransformed to several
metabolites in vivo and in vitro (Harvey and Paton, 1986). Some
metabolites have been suggested to contribute to the psychoactivity of
the parent compound. We have previously found that
7-oxo-8-THC shows almost equivalent
pharmacological activity to 8-THC in mice,
whereas 7- and 7-hydroxy-8-THC were
without significant activity (Narimatsu et al., 1984). In the present
study, we try to clarify which CYP isoform(s) are the major enzyme(s)
responsible for the oxidation of 7- and
7-hydroxy-8-THC in humans.
A number of approaches have been developed for identification of the
human CYP isoforms involved in the metabolism of particular xenobiotics
in vitro (Birkett et al., 1993; Zhao et al., 1996; Nakamura et al.,
1998). The oxidation of 7- and
7-hydroxy-8-THC to
7-oxo-8-THC by microsomes from human
B-lymphoblastoid cells expressing human CYPs (i.e., CYPs 1A1, 1A2, 2A6,
2B6, 2C8, 2C9-Arg, 2C9-Cys, 2C19, 2D6-Met, 2D6-Val, 2E1, and 3A4) was
investigated. Among the human CYP isoforms tested, CYP3A4 showed the
highest oxidative activity of 7- and
7-hydroxy-8-THC to
7-oxo-8-THC. Furthermore, when the activity of
each CYP isoform used in this study was estimated for each of the
respective CYP contents of human liver microsomes, according to the
data given by Shimada et al. (1994), only CYP3A4 exhibited high
activity in the oxidation of 7- and
7-hydroxy-8-THC to
7-oxo-8-THC and the activities of other CYP
isoforms were almost abolished (data not shown). Troleandomycin has
been widely used as a probe to determine the role of CYP3A enzymes in
drug metabolism and procarcinogen activation catalyzed by human liver
microsomes (Shimada and Guengerich, 1989; Wang et al., 1991; Zhao et
al., 1996). Ketoconazole is also potent inhibitor of CYP3A and almost
completely abolished the catalytic activity at concentration 1 µM
(Baldwin et al., 1995; Newton et al., 1995). The 7- and
7-hydroxy-8-THC MALCO activities in human
liver microsomes were significantly inhibited by 100 µM
troleandomycin and 1 µM ketoconazole. Although microsomes containing
CYPs 1A1, 1A2, 2C8, and/or 2C9 were able to produce measurable amounts
of 7-oxo-8-THC from 7- and/or
7-hydroxy-8-THC, neither 7- nor
7-hydroxy-8-THC MALCO activities in human
liver microsomes were inhibited by 7,8-benzoflavone and sulfaphenazole,
which are selective inhibitors of the CYP1A and CYP2C (except CYP2C19)
subfamilies, respectively (Baldwin et al., 1995; Newton et al., 1995;
Ono et al., 1996). These results indicate that CYP3A4 is the major
enzyme responsible for 7- and
7-hydroxy-8-THC MALCO activities in human liver.
The CYP3A4-expressed microsomes showed comparable activities to P450
MDX-B purified from mouse liver microsomes as a major isoform of MALCO.
The cDNA-expressed CYP3A4 activities are about 10-fold greater than
human liver microsomal activities. Because CYP3A4 content averages 30%
of total CYP content in human liver, theoretically,
7-hydroxy-8-THC would be oxidized more rapidly
in human liver microsomes. The reason why human liver microsomal
activities are lower is unknown.
8-Hydroxy-9-THC is further hydroxylated at
C-11 or in the side chain, but is oxidized to
8-oxo-9-THC (Harvey et al., 1980; Burstein and
Shoupe, 1981). The C-11 position of 8- and
9-THC is metabolized by CYP2C in human liver
microsomes (Bornheim et al., 1992; Watanabe et al., 1995).
7-Hydroxy-8-THC and
7-oxo-8-THC might be transformed to other
metabolites, e.g., the 11- or side chain-hydroxylated metabolites, when
7-hydroxy-8-THC was incubated with human liver microsomes.
To confirm the involvement of CYP3A4 in the oxidation of
7-hydroxy-8-THC to
7-oxo-8-THC, an immunoinhibition study was
performed using anti-P450 MDX-B antibody that was purified from liver
microsomes of mice as a major enzyme of the MALCO and estimated CYP3A11
from NH2-terminal amino acid sequence and
catalytic properties. The antibody significantly inhibited both MALCO
activities in human liver microsomes. This result is consistent with
the results of the effects of inhibitors and lends support to the idea
that CYP3A4 is mainly involved in the MALCO activities in human liver microsomes.
Our results suggest that CYP3A is involved in the formation of
7-oxo-8-THC from 7- and
7-hydroxy-8-THC in humans as well as guinea
pigs (Matsunaga et al., 1997) and mice (Matsunaga et al., 1998).
Unfortunately, the various CYPs of the 3A subfamily are closely
related, and chemical inhibitors and the antibody used cannot
distinguish between CYP3A4 and CYP3A5 or CYP3A7. CYP3A4, however, is
the major CYP isoform present in the adult human liver (up to 60% of
total CYPs; average content, about 30% of total CYP (Shimada et al.,
1994). On the other hand, CYP3A5 and CYP3A7 appears to be
polymorphically expressed in the adult liver (Komori et al., 1990;
Schuetz et al., 1994; Hakkola et al., 1994) and, when present, to be
expressed at levels much lower than CYP3A4, whereas CYP3A7 is expressed
constitutively and often at high levels in fetal liver (Wrighton et
al., 1988; Komori et al., 1990).
Wood et al. (1988) have also reported that androstenedione formation
from epitestosterone, the 17-hydroxy epimer of testosterone, by P450b
(CYP2B1) proceeds exclusively through the gem-diol pathway, whereas androstenedione formation from testosterone by the same enzyme
may proceed through a combination of gem-diol and dual hydrogen abstraction pathways. In the present study,
18O derived from atmospheric oxygen was
incorporated into 35 and 12%, respectively, of
7-oxo-8-THC formed from 7- or
7-hydroxy-8-THC when the substrates were
incubated with CYP3A4-expressed microsomes under
18O2. This result is
consistent with the observations obtained with P450GPF-B (Matsunaga et
al., 1997). The incorporation of 18O derived from
atmospheric oxygen molecule into the oxidative metabolite from
7-hydroxy-8-THC is significantly lower than
that from epitestosterone (84% enrich) reported by Wood et al. (1988),
although the incorporation of 18O after the
metabolism of 7-hydroxy-8-THC as well as
testosterone is negligible. It is suggested that in the
CYP3A4-catalyzed oxidation of
7-hydroxy-8-THC to
7-oxo-8-THC in an
18O2 atmosphere a
gem-diol intermediate is formed, which undergoes a
stereoselective loss of water from the -face. These results strongly
suggest that the mechanism of P450GPF-B and CYP3A4 may be comparable.
These results indicate that the formation of
7-oxo-8-THC from 7- and
7-hydroxy-8-THC in human liver microsomes
is catalyzed by CYP3A4. In the present study, only one substrate
concentration of 7- and 7-hydroxy-8-THC
was used to examine the role of CYPs metabolite formation. The
contribution of enzymes to some reactions can be altered by the
experimental conditions used, such as substrate concentration (Kariya
et al., 1996). Further extensive studies at higher/lower substrate
concentrations are required to clarify the contribution of other CYP isoforms.
| |
Footnotes |
|---|
Received October 6, 1999; accepted July 24, 2000.
This work was partially supported by a grant-in-aid for scientific research from the Ministry of Education, Science, and Culture of Japan, and by the Special Research Fund of Hokuriku University.
Send reprint requests to: Dr. Ikuo Yamamoto, Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, 920-1181, Japan. E-mail: i-yamamoto{at}hokuriku-u.ac.jp
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Abbreviations |
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Abbreviations used are: THC, tetrahydrocannabinol; CYP, cytochrome P450; MALCO, microsomal alcohol oxygenase; GC/MS, gas chromatography/mass spectrometry.
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References |
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Top
Abstract
Introduction
Experimental Procedures
Results
Discussion
References
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1-tetrahydrocannabinol.
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Humana Press, New Jersey.9- and 8-tetrahydrocannabinols by human liver microsomes.
J Pharmacobio-Dyn
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Chem Pharm Bull
31:
1784-1787.This article has been cited by other articles:
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, 
) or
7
, 
) in the presence of an
NADPH-generating system. 7