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Department of Biology, Indiana University-Purdue University at Indianapolis, Indianapolis, IN 46202
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ABSTRACT |
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 TOP ABSTRACT Monoterpene biochemistry.Monoterpene metabolism and...Antitumor activity of...Mechanisms of action of...REFERENCES |
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KEY WORDS: • chemoprevention • rats • hamsters • chemotherapy • isoprenoid
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Monoterpene biochemistry. |
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TOPABSTRACTMonoterpene biochemistry.Monoterpene metabolism and...Antitumor activity of...Mechanisms of action of...REFERENCES |
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), and
they are largely responsible for the distinctive fragrance of many
plants. These 10 carbon isoprenoids are derived from the mevalonate
pathway in plants but are not produced by mammals, fungi or other
species. In citrus fruits (Chayet et al. 1977
), peppermint and other
plants, d-limonene (p-mentha-1,8-diene;
Fig. 1
)is formed by the cyclization of geranylpyrophosphate in a reaction
catalyzed by limonene synthase (Alonso et al. 1992
, Kjonaas and Croteau 1983
). Limonene then serves as a precursor to a host of other
oxygenated monocyclic monoterpenes such as carveol, carvone, menthol,
perillyl alcohol and perillaldehyde (Karp et al. 1990
, McGarvey and Croteau 1995
; Fig. 1
).
|
). Orange oil, naturally
consisting of 90–95% d-limonene, is a commercially
available food flavoring agent. Furthermore, because of its pleasant
citrus fragrance, d-limonene is commonly added to cosmetics,
soaps and other cleaning products. Thus, human exposure to monoterpenes
through the diet or environment is widespread. Yet, limited information
is available for the estimation of monoterpene intake. The
d-limonene content of orange juice is ~100 ppm, or 0.01%
(NTP 1990
). |
Monoterpene metabolism and disposition. |
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TOPABSTRACTMonoterpene biochemistry.Monoterpene metabolism and...Antitumor activity of...Mechanisms of action of...REFERENCES |
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and 1976
, Phillips et al. 1995). In rats, the appearance of limonene
and its metabolites is evident within 20 min after its administration
by gavage (Crowell et al. 1992b
). Limonene and/or its metabolites are
detectable in serum, liver, lung and many other tissues (Igimi et al. 1974
), with higher concentrations detected in adipose tissue and
mammary gland than in less fatty tissues (Crowell et al. 1992b
). The
half-life of limonene in both rats and humans has been estimated to be
12–24 h (Crowell et al. 1992b
), and excretion occurs primarily through
the urine (Igimi et al. 1974
, Kodama et al. 1974
and 1976
).
Limonene is metabolized to oxygenated metabolites in rats and in
humans. In rats, the two major serum metabolites of limonene are
perillic acid and dihydroperillic acid (Crowell et al. 1992b
). Humans
produce these two serum metabolites as well as limonene-1,2-diol
(Crowell et al. 1994a
). These metabolic reactions have, in some cases,
been recapitulated in in vitro assays of limonene metabolism by liver
microsomes (Watabe et al. 1980
). In addition, glycine and glucuronide
conjugates of perillic acid and uroterpenol
(p-mentha-8,9-diol) have been detected in the urine of many
limonene-fed mammals (Kodama et al. 1974
and 1976
, Regan and Bjeldanes
1976
), suggesting that limonene is metabolized by both Phase I and
Phase II enzymes.
The metabolism of perillyl alcohol (Fig. 1)
is similar to that of
limonene. Metabolites, but not the parent drug, are detectable within
10 min after oral administration of perillyl alcohol (Phillips et al. 1995
). The predominant serum metabolite of perillyl alcohol in rats and
in dogs is perillic acid, and dihydroperillic acid is detectable in
lesser amounts (Haag and Gould 1994
, Phillips et al. 1995
).
Interestingly, higher serum concentrations of perillic acid have been
observed in rats fed 2% perillyl alcohol than in rats fed five times
as much limonene, suggesting a possible difference in pharmacokinetics
between the two drugs (Haag and Gould 1994
). The half-life of perillyl
alcohol in dogs given 250 mg/kg body weight is 3.2 h. At this
dose, perillyl alcohol causes no observable toxicity, and serum
perillic acid concentrations are present in excess of those reported
for rats receiving chemotherapeutic doses of the drug (Haag and Gould 1994
, Phillips et al. 1995
).
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Antitumor activity of monoterpenes. |
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TOPABSTRACTMonoterpene biochemistry.Monoterpene metabolism and...Antitumor activity of...Mechanisms of action of...REFERENCES |
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); dietary limonene also reduces
the incidence of spontaneous lymphomas in p53-/- mice
(Hursting et al. 1995
). Furthermore, when administered either in pure
form or as orange peel oil (95% d-limonene), limonene
inhibits the development of chemically induced rodent mammary (Elegbede et al. 1984
, Elson et al. 1988
, Maltzman et al. 1989
, Wattenberg 1983
),
skin (Elegbede et al. 1986b
), liver (Dietrich and Swenberg 1991
), lung
and forestomach (Wattenberg et al. 1989
and 1991
) cancers (reviewed in
Crowell and Gould 1994
; Elson and Yu 1994
, Elson 1995
). In rat mammary
carcinogenesis models, the chemopreventive effects of limonene are
evident during the initiation phase of
7-12-dimethylbenz[a]anthracene (DMBA)2-induced cancer (Elson et al. 1988
) and during the
promotion phase of both DMBA- and nitrosomethylurea (NMU)-induced
cancers (Elson et al. 1988
, Maltzman et al. 1989
). Dietary limonene
also inhibits the development of ras oncogene–induced
mammary carcinomas in rats (Gould et al. 1994
). Recently, Kawamori et al. (1996)
reported that the development of azoxymethane-induced
aberrant crypt foci in the colon of rats was significantly reduced when
they were given 0.5% limonene in the drinking water.
Caraway seed oil, and its principal monoterpene, carvone, prevent
chemically induced lung and forestomach carcinoma development when
administered before the carcinogen (Wattenberg et al. 1989
). In
addition, carveol (Crowell et al. 1992a
) and menthol (Russin et al. 1989
) have chemopreventive activity against DMBA-induced rat mammary
cancer when fed as 1% of the diet only during the initiation phase.
Geraniol, an acyclic dietary monoterpene, has in vivo antitumor
activity against murine leukemia, hepatoma and melanoma cells (Shoff et al. 1991
, Yu et al. 1995
) when administered before and after tumor cell
transplantation. In addition, perillyl alcohol has promotion phase
chemopreventive activity against chemically induced liver cancer in
rats (Mills et al. 1995
) and is very effective at preventing tumor
recurrences or secondary tumors in animals treated in a chemotherapy
regimen (Haag and Gould 1994
).
Dietary monoterpenes have promising chemotherapeutic activity against
established rodent pancreatic and mammary tumors. Both limonene
(Elegbede et al. 1986a
, Haag et al. 1992
) and perillyl alcohol (Haag and Gould 1994
) have chemotherapeutic activity against rat mammary
tumors, causing the complete regression of >80% of established DMBA-
or NMU-induced mammary carcinomas. Chander et al. (1994)
reported that
combination chemotherapy of NMU-induced rat mammary tumors with
limonene and the aromatase inhibitor 4-hydroxyandrostenedione was more
effective than either drug alone. Perillyl alcohol has chemotherapeutic
activity against pancreatic cancer at doses that cause little toxicity
to the host (Stark et al. 1995
). Perillyl alcohol reduced the growth of
transplanted hamster pancreatic tumors to less than half that of
controls. Moreover, a significant portion of perillyl alcohol–treated
pancreatic tumors completely regressed, whereas none of the control
tumors regressed (Stark et al. 1995
). Phase I clinical trial testing of
the cancer chemotherapeutic activity of limonene (McNamee 1993
) and
perillyl alcohol (Phillips et al. 1995
) is in progress.
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Mechanisms of action of monoterpenes. |
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TOPABSTRACTMonoterpene biochemistry.Monoterpene metabolism and...Antitumor activity of...Mechanisms of action of...REFERENCES |
|---|
). Blocking
chemopreventive agents act during the initiation phase of
carcinogenesis to prevent the interaction of chemical carcinogens with
DNA, e.g., by modulating carcinogen metabolism to less toxic forms.
Suppressing chemopreventive agents, on the other hand, act during the
promotion phase of carcinogenesis to prevent the outgrowth of initiated
cells. The blocking chemopreventive effects of limonene and other
monoterpenes during the initiation phase of mammary carcinogenesis are
likely due to the induction of Phase I and Phase II
carcinogen-metabolizing enzymes, resulting in carcinogen
detoxification. Chemopreventive doses of dietary limonene induce total
cytochrome P450 (Ariyoshi et al. 1975
, Austin et al. 1988
, Maltzman et al. 1991
). The specific cytochrome P450 isozymes induced by limonene
include CYP 2B1 and CYP2C (Maltzman et al. 1991
). Both limonene and
sobrerol, another chemopreventive monoterpene (Crowell 1992a
), induce
epoxide hydratase as well (Maltzman et al. 1991
). Ironically, a
comparative analysis of DMBA metabolism in control, limonene-, and
sobrerol-treated rats revealed that more of the proximate carcinogen is
produced in monoterpene-treated animals than in controls (Maltzman et al. 1991
). However, these effects are overcome by the induction of
glutathione-S-transferase and UDP-glucuronyl transferase by limonene
and sobrerol (Elegbede et al. 1993
). The net result is that fewer
DMBA-DNA adducts are formed in monoterpene-treated rats than in
controls, and more DMBA is excreted in the urine (Maltzman et al. 1991
). These results correlate well with the reduction in tumor
incidence and multiplicity observed in rats treated with dietary
limonene or sobrerol during the initiation phase of DMBA-induced
mammary cancer (Crowell et al. 1992a
, Elson et al. 1988
).
The cancer suppressing chemopreventive activity of monoterpenes during
the promotion phase of mammary and liver carcinogenesis may be due to
inhibition of tumor cell proliferation, acceleration of the rate of
tumor cell death and/or induction of tumor cell differentiation (Morse and Stoner 1993
). The chemopreventive activity of perillyl alcohol
during the promotion phase of liver carcinogenesis is associated with a
marked increase in tumor cell death by apoptosis, or programmed cell
death (Mills et al. 1995
). Under the same conditions, there is no
detectable effect of perillyl alcohol on BrDU incorporation into DNA, a
measure of cell proliferation (Mills et al. 1995
). Chemotherapy of
chemically induced mammary tumors with monoterpenes results in tumor
remodeling or redifferentiation (Haag et al. 1992
, Haag and Gould 1994
). Similarly, perillyl alcohol promotes the differentiation of
cultured neuro2A cells (Shi and Gould 1995
). Expression of the
mannose-6-phosphate-insulin-like growth factor II receptor and
transforming growth factor ß1 (TGFß) is increased in the
limonene-treated, regressing mammary tumors, but not in the small
number of tumors that are unresponsive to limonene (Jirtle et al. 1993
), suggesting that limonene-induced tumor cell
remodeling/redifferentiation is TGFß-dependent.
Monoterpenes have multiple pharmacologic effects on mevalonate
metabolism; some of these effects may account for their tumor
suppressive activity (Elson 1995
). Some monoterpenes, including
limonene and menthol, inhibit hepatic 3-hydroxy-3-methylglutaryl (HMG)
CoA-reductase activity (Clegg et al. 1980 and 1982
) and reduce serum
cholesterol (Qureshi et al. 1988
). More recently, perillyl alcohol has
been shown to inhibit ubiquinone and cholesterol biosynthesis in
cultured NIH3T3 cells (Ren and Gould 1994
). In this cell system, the
inhibition of cholesterol biosynthesis occurred at the conversion of
lathosterol to cholesterol, i.e., downstream of HMG CoA reductase.
Many monoterpenes, including limonene, perillyl alcohol and their
active serum metabolites inhibit protein isoprenylation (Crowell et al. 1991 and 1994b
, Gelb et al. 1995
, Kawata et al. 1994
, Schulz et al. 1994
). Protein isoprenylation involves the post-translational
modification of a protein by the covalent attachment of a lipophilic
farnesyl or geranylgeranyl isoprenoid group to a Cys residue at or near
the carboxyl terminus (Clarke 1992
). Isoprenoid substrates for
prenyl:protein transferase enzymes include farnesylpyrophosphate and
geranylgeranylpyrophosphate, two intermediates in the mevalonate
pathway (Goldstein and Brown 1990
). Monoterpenes can directly inhibit
prenyl-protein transferases in vitro (Gelb et al. 1995
) at doses that
are attainable in vivo (Crowell et al. 1992b and 1994a
, Haag and Gould 1994
, Phillips et al. 1995
), suggesting that the inhibition of protein
prenylation by monoterpenes occurs at the level of prenyl-protein
transferase enzymes.
Known mammalian prenylated proteins include Ras-related small
GTP-binding proteins, heterotrimeric G proteins and nuclear lamins
(Clarke 1992
). Prenylation of Ras enables it to associate with the
plasma membrane, which is required for its oncogenic activity (Kato et al. 1992
). Many prenylated proteins regulate cell growth and/or
transformation (Clarke 1992
), and impairment of the prenylation of one
or more of these proteins might account for the antitumor activity of
monoterpenes. However, recent studies suggest that the main target of
these effects may not be Ras itself. Ruch and Sigler (1994)
found that
growth inhibition of ras-transformed liver epithelial cells
was attained at doses that do not affect the association of Ras with
membranes. In addition, Gould et al. (1994)
reported that limonene
prevented the formation of mammary tumors expressing normal or
oncogenic ras genes with equal efficiency. Together, these
data suggest that either the antitumor activity of monoterpenes is due
to prenylation-independent mechanisms or, alternatively, that
prenylation of proteins other than Ras may be affected by monoterpenes.
Evidence for the latter hypothesis includes the observation that the
prenylation of many proteins, in addition to Ras, is affected by
monoterpenes in a variety of cell types (Crowell et al. 1991 and 1994b
,
Kawata et al. 1994
, Schulz et al. 1994
). Moreover, recent evidence
indicates that, like Ras proteins, the prenylated proteins TC21 (Graham et al. 1994
), Rho (Perona et al. 1993
) and the PRL-1/PTPCAAX tyrosine
phosphatases (Crowell et al. 1996) can be oncogenic as well, suggesting
that they may be important cellular targets of antitumorigenic protein
prenylation inhibitors such as monoterpenes.
In summary, a variety of dietary monoterpenes have been shown to be effective in the chemoprevention and chemotherapy of cancer. Now, monoterpene research is progressing into human clinical trials for chemotherapeutic activity. Monoterpenes also possess many characteristics of ideal chemopreventive agents, namely, efficacious antitumor activity, commercial availability, low cost, oral bioavailability and low toxicity, making it feasible to begin considering them for human cancer chemoprevention testing.
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FOOTNOTES |
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2 Abbreviations used: DMBA,
7-12-dimethylbenz[a]anthracene; HMG,
3-hydroxy-3-methylglutaryl; NMU, nitrosomethylurea; TGF, transforming
growth factor.
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REFERENCES |
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TOPABSTRACTMonoterpene biochemistry.Monoterpene metabolism and...Antitumor activity of...Mechanisms of action of...REFERENCES |
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