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PubMed1992

Purification of 4S-limonene synthase, a monoterpene cyclase from the glandular trichomes of peppermint (Mentha x piperita) and spearmint (Mentha spicata).

The p-menthane monoterpenes of the Mentha species are biosynthesized from geranyl pyrophosphate via the monocyclic olefin 4S-limonene. A monoterpene cyclase was isolated from both Mentha x piperita (peppermint) and Mentha spicata (spearmint) that catalyzes the cyclization of geranyl pyrophosphate to 4S-limonene. This enzyme, 4S-limonene synthase, was purified to apparent homogeneity by dye ligand, anion exchange, and hydrophobic interaction chromatography. Since the monoterpenes of Mentha are synthesized and secreted in modified epidermal hairs called glandular trichomes, an extract of isolated glandular trichome cells was used as the source of this enzyme. A combination of gel permeation chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that purified 4S-limonene synthase had a native molecular weight of 56,000 and was monomeric. The principal product of the enzyme was enantiomerically pure (-)-4S-limonene, and a catalytic constant of 0.3/s was determined. The basic properties of 4S-limonene synthase from both M. x piperita and M. spicata are identical and, in general, are similar to those of other monoterpene, sesquiterpene, and diterpene cyclases isolated from microorganisms and higher plants.

Chromatography, Liquid↗
PubMed1996

Partial purification and characterization of a monoterpene cyclase, limonene synthase, from the liverwort Ricciocarpos natans.

4S-(-)-limonene is the major monoterpene accumulated by the liverwort Ricciocarpos natans, and a cell-free extract from this nonvascular plant cultured in vitro catalyzes the cyclization of geranyl diphosphate to limonene. The time course of limonene synthase activity parallels cultured growth but shows a maximum in specific activity in the lag phase following transfer to fresh medium. The operationally soluble enzyme was partially purified by combination of anion-exchange and hydroxylapatite chromatography. The limonene synthase from R. natans possesses a molecular weight of about 51,000, exhibits a pH optimum at 6.5, a pI at 5.3, and a requirement for either Mg2+ or Mn2+ as cofactor, and appears to employ 3S-linalyl disphosphate as a bound intermediate in the cyclization of the geranyl substrate (Km approximately 1.25 microM). In stereochemistry of the coupled isomerization-cyclization reaction and in general properties, the limonene synthase from this bryophyte resembles the corresponding monoterpene cyclases from gymnosperm and angiosperm species.

Cyclohexenes↗
PubMed1994

Hydroperoxides in oxidized d-limonene identified as potent contact allergens.

Hydroperoxides of d-limonene were shown to be potent contact allergens when studied in guinea-pigs. Limonene-2-hydroperoxide (2-hydroperoxy-p-mentha-6,8-diene, a mixture of trans and cis isomers) was synthesized for the first time. The ratio between the trans and cis forms was 3:1. These two hydroperoxides were identified as the major hydroperoxides in autoxidized d-limonene. In photo-oxidized d-limonene, they constituted a minor part of the hydroperoxide fraction. Hydroperoxides may bind to proteins of the skin to make antigens either via a radical mechanism or after reactions to give epoxides. The cross-reactivity between the epoxide limonene-1,2-oxide, a potent contact allergen, and the hydroperoxides was therefore studied. No significant pattern of cross-reactivity was found. Further studies to identify and test the allergenicity of single hydroperoxides are needed to elucidate the mechanism of the allergenicity.

Allergens↗
PubMed1994

Mammary carcinoma regression induced by perillyl alcohol, a hydroxylated analog of limonene.

The monoterpene perillyl alcohol has been shown to induce the regression of 81% of small mammary carcinomas and up to 75% of advanced mammary carcinomas initiated by 7,12-dimethylbenz(a)anthracene (DMBA) in the Wistar-Furth rat. Dietary perillyl alcohol was greater than 5 times more potent than the monoterpene limonene at inducing tumor regression. Perillyl alcohol is rapidly metabolized in the rat, as is limonene. Rats chronically fed perillyl alcohol had the same circulating plasma metabolites as rats fed limonene; however, the levels of these metabolites found in the plasma were higher for perillyl alcohol-fed rats. For example, rats given a 2% perillyl alcohol diet for 10 weeks had plasma levels of terpene metabolites of 0.82 mM whereas those fed a 10% limonene diet for the same period had blood levels of 0.27 mM. It thus appears that the increased potency of perillyl alcohol over limonene in causing tumor regression may be due at least in part to differences in the pharmacokinetics of these two monoterpenes. We feel that perillyl alcohol is a good candidate for clinical testing of anticancer efficacy in humans.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Comparison of short-term renal effects due to oral administration of decalin or d-limonene in young adult male Fischer-344 rats.

Groups of young adult male Fischer-344 rats given the vehicle (corn oil) or either decalin or d-limonene at dose levels of 75, 150 or 300 mg/kg body weight by a single daily gavage on 5 days/wk were killed on study days 6 or 27, approximately 24 hr after the fifth or 20th dose, to determine whether the specific time- and dose-related triad of renal alterations characterizing decalin-associated nephrotoxicity in the adult male rat also occurs in response to d-limonene. Dose-related hyaline droplet formation associated with renal accumulation of a specific protein alpha 2u-globulin) is considered the primary response in the morphogenesis of decalin-induced nephrotoxicity in the male rat and was present to a maximal degree in all decalin- and d-limonene-treated groups by day 6. Alterations considered to be sequelae of the hyaline droplet response, including granular casts in the outer zone of the medulla and multiple cortical changes collectively classified as chronic nephrosis, were present in the kidneys of both decalin- and d-limonene-treated rats killed on day 27. These findings demonstrate a uniformity of primary and secondary renal responses to the two chemicals, strongly suggesting that the morphogenesis of d-limonene-associated nephrotoxicity in the adult male rat is consistent with that of decalin. The response of the male rat kidney to decalin treatment has been shown to be uniquely different, by virtue of anatomical, physiological and biochemical peculiarities involving the proximal convoluted tubule, from that in female rats and higher mammalian species.

Animals↗
PubMed1990

Assessment of the subchronic oral toxicity of d-limonene in dogs.

Several hydrocarbons, including d-limonene, have been shown to produce a male-rat-specific nephrotoxicity that is manifested acutely as exacerbation of hyaline droplet formation. In a study to assess the presence or absence of this response in a non-rodent species, the dog was selected as a relevant model because of an earlier report suggesting that d-limonene may be nephrotoxic in this species. Five male and five female adult beagle dogs per treatment group were gavaged twice daily over a 6-month period with tap-water (control) or d-limonene at 0.12 or 1.2 ml/kg body weight/day (100 or 1000 mg/kg body weight/day). The highest daily dose was determined in a pilot study to be close to the maximum tolerated dose for emesis (ED50 1.6 ml/kg body weight). The test compound was administered in divided doses to minimize the incidence of emesis. Feed consumption and body weight were unaffected by treatment. Linear regression analyses indicated a positive dose-related trend for absolute and relative female kidney weight and relative male kidney weight. There were no histopathological changes in the kidneys, evaluated by both haematoxylin and eosin and Mallory-Heidenhain staining, that could be associated with the organ-weight changes. Furthermore, there was no evidence of hyaline droplet accumulation nor of any other sign of hydrocarbon-induced nephropathy typical of those seen in male rats treated with d-limonene. Thus, dogs are refractory to the hyaline droplet nephropathy observed in male rats, thereby providing additional evidence that the male rat kidney is uniquely sensitive to hydrocarbons like d-limonene, and that this specific male rat nephropathic response may be inappropriate for interspecies extrapolation and human risk assessment.

Administration, Oral↗
PubMed2005

The effect on human eye blink frequency of exposure to limonene oxidation products and methacrolein.

Oxidation products of terpenes (e.g. limonene) contain unidentified irritants, which may be responsible for a fraction of the reported eye and airway complaints in indoor environments. Here we report exposure to parts per billion (ppb) levels of limonene oxidation products (LOPs) and the terpene oxidation product methacrolein using blink frequency (BF) as a measure of trigeminal stimulation of the human eye. Ten male subjects averaging 43 (standard deviation 10.5) years were exposed for 20 min to LOPs, methacrolein, and clean air, respectively. A baseline BF was measured prior to and following each exposure (8 min and 4 min, respectively). The subjects were exposed locally in the non-dominant eye and single blind at 20% relative humidity (RH), while viewing an educational film. Blinking was video recorded and evaluated for full sessions of 36 min. Mean BF increased significantly during exposure to LOPs and methacrolein compared to the baseline of clean air, and the findings coincided with weak eye irritation symptoms. Lowest observed effect levels were 286 ppb methacrolein and a 10-min-old LOPs mixture of initially 92 ppb limonene and 101 ppb ozone (O3), which increased the BF comparably by 18% (p=0.001) and 17% (p=0.003), respectively. The increase in BF was smaller, although not significantly different, during exposure to LOPs at 50% RH to 20% RH in mixtures prepared from ca. 350 ppb limonene and 300 ppb O3. LOPs may cause trigeminal stimulation and possibly eye irritation at O3 and limonene concentrations, which are close to high-end values measured in indoor settings. The effects may be exacerbated by low RH.

Acrolein↗
PubMed1999

Inhibition of protein prenylation by metabolites of limonene.

The monoterpenes limonene and perillyl alcohol are undergoing clinical evaluation in cancer patients. In this paper, we report the chemical synthesis, characterisation, and quantitation in patients' plasma of a novel human metabolite of limonene, which is identified as an isomer of perillic acid. The synthesis of R-perillic acid is also described, because previous reports on the activity of perillic acid against isoprenylation enzymes refer to the S-enantiomer, although it is the R-enantiomer which is the metabolite of R-limonene. The above monoterpenes, with several related compounds, were assayed for inhibitory activity towards the isoprenylation enzymes in rat brain cytosol. Although R- and S-limonene are only weak inhibitors of the isoprenylation enzymes, their major metabolites, perillic acid and perillyl alcohol, are more potent inhibitors, with IC50 values in the low mM range. The metabolites possess greater activity towards the geranylgeranyltransferase type I enzyme than farnesyltransferase, while the novel metabolite displays IC50 values similar to those of perillic acid suggesting that it may contribute to the in vivo activity of limonene.

Alkyl and Aryl Transferases↗
PubMed1997

d-Limonene inhibits N-nitrosobis(2-oxopropyl)amine induced hamster pancreatic carcinogenesis.

The effect of d-limonene on pancreatic carcinogenesis induced by N-nitrosobis(2-oxopropyl)amine (BOP) was investigated in Syrian golden hamsters. During and after 5 weekly injections of BOP, each hamster was fed diet containing d-limonene. In week 26, quantitative histological analysis showed that prolonged treatment with d-limonene significantly reduced the number of pancreatic carcinomas. Administration of d-limonene did not cause a significant increase in the apoptotic index, but caused a significant decrease in the BrdU labeling index of carcinoma. These findings indicate that d-limonene inhibits the development of pancreatic carcinoma not by enhancing tumor cell loss through apoptosis, but rather by inhibiting cell proliferation.

Animals↗
PubMed1999

Inhibition by D-limonene of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

The effect of prolonged oral administration of D-limonene on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and on the labeling and apoptotic indices of gastric cancers were investigated in Wistar rats. After 25 weeks of the carcinogen treatment, rats were given chow pellets containing 1% or 2% limonene. In week 52, long-term oral administration of 2%, but not 1%, limonene significantly decreased the incidence of gastric cancers. Limonene also significantly decreased the labeling index and significantly increased the apoptotic index of gastric cancers. No K-ras mutations were detected in gastric cancers induced by MNNG in either group. These findings indicate that limonene inhibits the development of gastric cancers through increased apoptosis and decreased DNA synthesis of gastric cancers, but not through ras oncoprotein plasma membrane association.

Adenocarcinoma↗
PubMed2006

Analysis of secondary organic aerosol compounds from the photooxidation of d-limonene in the presence of NOx and their detection in ambient PM2.5.

Chemical analysis of secondary organic aerosol (SOA) from the photooxidation of a d-limonene/NOx/air mixture was carried out. SOA, generated in a smog chamber, was collected on Zefluor filters. To determine the structural characteristics of the compounds, the filter samples were solvent extracted and derivatized using analytical techniques that characterize functional groups contained in the compound: BF3-methanol derivatization was used for carboxylic groups, BSTFA for acidic and nonacidic hydroxyl groups, and PFBHA for ketone and aldehyde groups. The resulting derivative compounds were analyzed by GC-MS in the methane Cl and El modes. GC-MS analysis showed the occurrence of 103 oxygenated organic compounds in the filter extracts, 28 of which were identified. The major components include five tracer compounds previously identified from the photooxidation of alpha-pinene/NOx or beta-pinene/NOx systems, C4-C6 linear dicarboxylic acids, ketolimononaldehyde, limonic acid, and ketolimonic acid. Time profiles, yields, and proposed reaction schemes are provided for selected compounds. The laboratory SOA yield was 0.51 at a SOA concentration of 1470 microg m(-3). To determine the contributions of SOA products from d-limonene to ambient PM2.5, an analysis was performed for eight ambient PM2.5 samples collected in the southeastern United States in summer 2003. GC-MS analysis showed the occurrence of 21 d-limonene SOA compounds, indicating the impact of d-limonene on the regional aerosol burden. Based on our analysis, two compounds (nos. 55 and 69), not observed from the photooxidation of alpha-pinene or beta-pinene, are candidate tracers for d-limonene in atmospheric particulate matter.

Aerosols↗
PubMed2006

Secondary organic aerosol formation from limonene ozonolysis: homogeneous and heterogeneous influences as a function of NO(x).

Limonene has a high emission rate both from biogenic sources and from household solvents. Here we examine the limonene + ozone reaction as a source for secondary organic aerosol (SOA). Our data show that limonene has very high potential to form SOA and that NO(x) levels, O(3) levels, and UV radiation all influence SOA formation. High SOA formation is observed under conditions where both double bonds in limonene are oxidized, but those conditions depend strongly on NO(x). At low NO(x), heterogeneous oxidation of the terminal double bond follows the initial limonene ozonolysis (at the endocyclic double bond) almost immediately, making the initial reaction rate limiting. This requires a high uptake coefficient between ozone and the first-generation, unsaturated organic particles. However, at high NO(x), this heterogeneous processing is inhibited and gas-phase oxidation of the terminal double bond dominates. Although this chemistry is slower, it also yields products with low volatility. UV light suppresses production of the lowest volatility products, as we have shown in earlier studies of the alpha-pinene + ozone reaction.

Aerosols↗
PubMed1994

Modulation of the mevalonate pathway and cell growth by pravastatin and d-limonene in a human hepatoma cell line (Hep G2).

Modulation of cell growth by a combination of pravastatin [a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor] and d-limonene (an inhibitor of protein isoprenylation) was studied using Hep G2, a human hepatoma-derived cell line. Pravastatin, at 0.1 mM, produced 85% inhibition of cholesterol biosynthesis in Hep G2 cells. The combination of 0.1 mM pravastatin and 1.0 mM d-limonene had no further effect on the reduction seen with pravastatin alone. Addition of 0.1 mM pravastatin or 1.0 mM d-limonene did not significantly suppress DNA synthesis by the cells, whereas the combination suppressed it to 50% of the control level. Production of m-p21ras was markedly decreased to 35% of the control level by the combination of these two inhibitors. Both the reduction by pravastatin of farnesylpyrophosphate as substrate for protein:farnesyl transferase and inhibition of protein farnesylation by d-limonene seem to be responsible for the profound suppression of m-p21ras formation in the cells. However, dolichol synthesis was not suppressed by the combination of these inhibitors. In human fibroblasts, the combination suppressed m-p21ras production but not DNA synthesis. These findings suggest that the combination of pravastatin and d-limonene acts on cancer cell growth through inhibition of the post-translational processing of cellular proteins including p21ras, rather than through the suppression of cholesterol and dolichol biosynthesis. Thus, the combination of an HMG-CoA reductase inhibitor and an inhibitor of protein isoprenylation offers potential as a new approach for cancer therapy.

Antineoplastic Agents↗
PubMed1993

d-limonene exposure to humans by inhalation: uptake, distribution, elimination, and effects on the pulmonary function.

The toxicokinetics of d-limonene were studied in human volunteers exposed by inhalation (2 h, work load 50 W) in an exposure chamber on three different occasions. The exposure concentrations were approximately 10, 225, and 450 mg/m3 d-limonene. The relative pulmonary uptake was high, approximately 70% of the amount supplied. The blood clearance of d-limonene observed in this study, 1.1 l kg-1 h-1, indicates that d-limonene is metabolized readily. About 1% of the total uptake was eliminated unchanged in the expired air after the end of exposure, while approximately 0.003% was eliminated in the urine. A long half-time in blood was observed in the slow elimination phase, which indicates accumulation in adipose tissues. A decrease in vital capacity was observed after exposure to d-limonene at a high exposure level. The subjects did not experience any irritative symptoms or symptoms related to the central nervous system (CNS).

Administration, Inhalation↗
PubMed1994

Influence of an anti-oxidant on the formation of allergenic compounds during auto-oxidation of d-limonene.

Butylated hydroxytoluene (BHT), a common anti-oxidant, was added to different samples of d-limonene. The decrease in concentration of d-limonene and the formation of oxidation products were compared between the samples and with samples without anti-oxidant using gas chromatography. The aim of the study was to investigate how long d-limonene to which BHT was added could be handled when air-exposed at room temperature, without formation of oxidation products which according to previous studies increase the risk of skin sensitization. In experiments trying to mimic the handling of limonene products at workplaces the addition of BHT prevented auto-oxidation for periods depending on the purity of the products and on the room temperature. Cold and dark storage of d-limonene in closed vessels prevented auto-oxidation for 1 year without addition of anti-oxidant.

Air Pollutants↗
PubMed1984

Inhibition of DMBA-induced mammary cancer by the monoterpene d-limonene.

We investigated whether the addition of d-limonene to the diets of rats would modify the process of mammary tumor induction by 7,12-dimethylbenz[a]anthracene (DMBA). When diets containing 1000 or 10 000 p.p.m. d-limonene were fed to rats from one week before DMBA administration to the end of the experiment (27 weeks post DMBA treatment), a significant reduction in mammary carcinogenesis was observed at each level. The inhibition of carcinogenesis was mainly due to an increase in latency; however, major differences in incidence could be seen during the follow-up period. For example, rats fed 10 000 p.p.m. of d-limonene had a 72% reduction in mammary tumors when compared to controls at 18 weeks post DMBA treatment. In addition to inhibiting the appearance of mammary tumors, d-limonene was also found to cause the regression of frank mammary tumors. No toxicity was evident in these rats even at the highest d-limonene dose. Control and all treated rats gained weight at the same rate throughout the experiment. In addition, no differences were found in their peripheral blood counts (Hct, total white cell and differential count).

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1992

Effect of d-limonene on the amounts of ethanol and indomethacin penetrated from aqueous gel ointments to rat skin.

The amounts of d-limonene, ethanol and indomethacin (IMC) which were transferred from aqueous gel ointments to the skin were determined in rats. The concentration of IMC in the skin correlated well with the plasma concentration of IMC percutaneously absorbed from the gel ointment. The increase of d-limonene concentration in the gel ointments was directly proportional to the accumulation of ethanol in the skin. The amount of ethanol in the skin was closely associated with the percutaneous absorption of IMC. As a possible mechanism for enhancement action of d-limonene and ethanol, it was considered that, at first, d-limonene penetrates into the skin under coexistence with ethanol and may change the barrier structure of the stratum corneum. The transfer of ethanol to the skin is thereby enhanced under the coexistence of d-limonene in the skin. Thus, the permeation of IMC can be promoted due to its affinity with ethanol.

Absorption↗
PubMed2005

Limonene, a citrus extract, for control of mealybugs and scale insects.

In a series of bioassays with mealybugs, aqueous solutions of 1% limonene were tested that used from 0.50 to 1.50% all purpose spray adjuvant (APSA)-80 as an emulsifier/surfactant. The two ingredients were added to water or to 0.1% Silwet L-77, an agricultural surfactant. Using 1% limonene, 0.75% APSA-80 and 0.1% Silwet L-77, a semitransparent mixture (primarily a microemulsion) was obtained that was safe for most plants and provided good control of mealybugs when sprayed or used in 1-min dips. Used at half strength, this mixture controlled > or =99% of whiteflies, whereas the full-strength mixture controlled from 69 to 100% of mealybugs and scales, including > or =93% control of root mealybugs. In side-by-side greenhouse tests, this mixture was superior to a 2% solution of insecticidal soap or a 2% solution of horticultural spray oil. Mortality of green scales on potted gardenia plants averaged 95, 89, and 88% on plants sprayed with limonene, insecticidal soap, or horticultural oil, respectively. In a related test, these same sprays killed 44.1, 22.7, or 12.5% of third and fourth instar clustering mealybugs, respectively. Limonene has promise as a safe, natural pesticide for insect pests on tolerant plants. Although 1% limonene solutions damaged certain species of ferns, gingers and delicate flowers, they caused no damage to ornamentals with thick, waxy leaves, such as palms, cycads, and orchids.

Animals↗