Perilla Ketone Research Articles

Comparison of the Pulmonary Dysfunction Caused by Cardiogenic and Noncardiogenic Pulmonary Edema

We designed a series of experiments to compare the pulmonary dysfunction observed in models of cardiogenic and noncardiogenic pulmonary edema in chronically instrumented awake sheep. Cardiogenic pulmonary edema was induced by inflating the balloon of a Foley catheter surgically positioned in the mitral valve orifice causing increased left atrial pressure (increases PLA). Noncardiogenic pulmonary edema was induced by intravenous infusion of Perilla ketone (PK). Calculated microvascular pressure remained constant during PK infusion but increased from 9.4 +/- 0.7 to 42.8 +/- 2.4 cm H2O during increases PLA. Comparable increases in lung lymph flow (QL) were observed in the two protocols (five to seven times baseline). Pulmonary edema as quantified by chest radiograph scores increased from 0 (normal) to 2.9 +/- 0.5 and 3.4 +/- 0.1 in the PK and increases PLA groups, respectively. Room air alveolar to arterial oxygen pressure difference (P[A-a]O2) increased from 24 +/- 3 to 46 +/- 7 mm Hg in the PK group and from 23 +/- 4 to 56 +/- 6 mm Hg in the increases PLA group. Dynamic compliance of the lungs (Cdyn) expressed as the percentage of the baseline value decreased to 53 +/- 7 and 50 +/- 7% in the PK and increases PLA groups, respectively. Resistance to airflow across the lungs (RL) increased from 2.5 +/- 0.6 to 3.3 +/- 0.8 cm H2O.L-1.sec-1 in the PK group and from 1.4 +/- 0.3 to 4.2 +/- 1.1 in the increases PLA group. Significant correlations were observed between changes in the severity of pulmonary edema observed on chest radiographs, Cdyn, delta P(A-a)O2, and QL in both the increases PLA groups. We conclude that similar degrees of pulmonary edema, regardless of the mechanism, are associated with similar changes in QL, Cdyn, and delta P(A-a)O2. Hydrostatic pulmonary edema appeared to cause greater changes in RL than that resulting from increased microvascular permeability.

Evaluation of perilla ketone-induced unilateral lung injury using external gamma scanning.

We used a modified external gamma scanning technique to quantitate right and left lung permeability changes to iodinated sheep albumin before and after perilla ketone (PK)-mediated unilateral lung injury in seven anesthetized sheep. Three portable gamma scintillation probes containing 2-in. NaI crystals detected radioactivities of 51Cr-labeled red blood cells and 125I-labeled albumin over the right and left lungs and blood, respectively. Radioactivities were monitored for 1 h before and 3 h after infusion of 25 mg/kg PK into a single lung. Calculation of normalized slope index (NSI) (Roselli and Riddle, J. Appl. Physiol. 67: 2343-2350, 1989) over the 30-min interval before PK and over the 60- to 90-min interval after PK for each lung revealed a four- to five-fold NSI increase in lungs receiving PK (0.00237 +/- 0.00065 to 0.0109 +/- 0.0016 min-1) and no increase in contralateral control lungs (0.00214 +/- 0.00065 to 0.00201 +/- 0.00032 min-1). Observed changes in NSI were consistent with postmortem evaluations of each lung. Lungs receiving PK had significantly higher wet-to-dry lung weight ratios and extravascular lung water volumes than contralateral control lungs. Measured bloodless wet-to-dry lung weight ratios were 5.68 +/- 0.39 and 3.27 +/- 0.27 (P < 0.05) for PK and control lungs, respectively.

Perilla ketone increases endothelial cell monolayer permeability in vitro

Perilla ketone (PK) is a potent lung toxin that causes increased microvascular permeability pulmonary edema in grazing animals. Because the mechanism of action of PK is not know, we investigated whether PK directly affects endothelial cells. Bovine aortic endothelial cells were grown to confluence on Cytodex-3 microcarrier beads and placed in a chromatographic cell column. Monolayer permeability was evaluated from the elution profiles of three optical tracers: blue dextran (2 x 10(6) mol wt), sodium fluorescein (NaF, 342 mol wt), and cyanocobalamin (B12, 1,355 mol wt). Perfusion with 1.2 mM PK increased permeability within 15 min to NaF and B12 by 51 +/- 6 and 54 +/- 11%, respectively. Permeability returned to baseline after PK removal. These in vitro results suggest that PK produces a rapid and reversible increase in endothelial permeability directly. Staining of fixed cells with rhodamine-phalloidin revealed a major disruption of actin microfilaments after PK treatment. Because previous reports suggested that PK may be activated via cytochrome P-450, we attempted to block this using the cytochrome P-450 inhibitor ketoconazole. Ketoconazole alone did not significantly affect permeability, and the combination of PK and ketoconazole resulted in permeability increases similar to those measured for PK alone. This suggests that PK may not require cytochrome P-450 to increase vascular permeability.

Foodborne toxicants affecting the lung

Foods contain several toxicants that can exert adverse effects on the lung. Some of these toxicants are naturally occurring substances such as the pyrrolizidine alkaloids, histamine, the sweet potato toxins, perilla ketone, paralytic shellfish toxins, the red tide toxins, and botulinum toxins. Other foodborne toxicants affecting the lungs are additives (nitrite, BHT, carrageenan), processing-induced toxicants (the agent involved in Spanish toxic oil syndrome, the mutagens from cooked meats), or environmental contaminants (paraquat, PCBs, PCDFs). Some of these toxicants have primary effects on other organ systems. For example, paralytic shellfish toxins, the red tide toxin, and botulinum toxins are primarily neurotoxins whose effects on the lung are secondary. The pyrrolizidine alkaloids primarily affect the liver. However, some of the toxicants exert their primary effects on the lung (paraquat, the sweet potato toxins, perilla ketone). For some of the foodborne toxicants affecting the lungs, these effects are only noted in experimental animals fed high doses of the toxicant for prolonged periods of time. Examples would include BHT, nitrite, and carrageenan. These particular chemicals are likely to be safe to consume under more normal circumstances of exposure.

A new simple route to furanic ketones; Preparation of Elsholtzione, naginata ketone and perilla ketone.

Copper- or iron-catalyzed acylation of organomanganese reagents allows to obtain 3- and 2-acylfurans in high yields. Elsholtzione, naginata ketone and perilla ketone have been prepared according to this procedure.

Effects of Perilla ketone on the in situ sheep lung.

We studied the effects of three different doses (15, 20, and 25 mg/kg) of Perilla ketone (PK) on the blood-perfused in situ sheep lung while obtaining external measurements of lung transvascular protein flux. Lymph flow and lymphatic protein clearance increased significantly after all doses of PK. Severe pulmonary edema was confirmed by high postmortem wet-to-dry lung weight ratios and increased extravascular lung water from multiple indicator-dilution studies. Urea permeability-surface area product and effective diffusivity from multiple indicator-dilution studies also increased after PK infusion. Because we observed no evidence of increased capillary pressure or increased microvascular surface area after PK, we conclude that PK significantly increased pulmonary microvascular permeability. Certain aspects of the in situ PK response appeared to be dose dependent. The lungs responded rather quickly to high doses of PK, but an apparent latency period was noted with low doses of PK. Postmortem wet-to-dry lung weight ratios were always high but did not suggest dose dependence. However, times of postmortem measurements were not the same for all doses of PK. The external scan technique appeared to be sensitive to changes that occurred in the lung after PK. Externally detected albumin interstitial-to-plasma mass (mass I/P) ratios were substantially higher after PK than during control in situ studies. In some experiments, final mass I/P ratios increased above 4 approximately 2.0 h after PK compared with control values of 0.2 and 0.4. A delay time between injection and change in mass I/P slope was also observed, which decreased with increasing dose of PK. PK causes a permeability injury in the in situ sheep lung and provides a useful model for studying the sensitivity of permeability measurement techniques such as the external gamma-ray detection method.

The effects of selected bulky substituents on the pulmonary toxicity of 3-furyl ketones in mice

Preliminary studies examined the toxicity of a series of simple alkyl 3-furyl ketone congeners of perilla ketone, 1-(3-furyl)-4-methylpentan-1-one (1), in mice, but little was known about how aromatic or bulky side chains might affect toxicity. Therefore, 3-furylphenyl ketone (2) 3-furylphenethyl ketone (3) and 1-3-furyl-4, 4-dimethylpentan-1-one (4) were synthesized to examine this problem. The 48-h LD50 (i.p.) in Notre Dame Swiss mice for each analog was greater than that of the parent toxicant, perilla ketone (1, 30 +/- 5; 2, 173 +/- 4; 3, 150 +/- 11; 4, 79 +/- 5 mumol/kg). Absorption and distribution of these compounds should be similar based on their lipophilicities. Preliminary evidence suggested that the reduced toxicities of 2, 3 and 4 compared with 1 cannot be explained on the basis of 13C-NMR (electron density) characteristics. Instead, the reduced potency likely is the result of steric hindrance of bioactivation by the bulky side chain substituents and(or) alternative metabolism on the phenyl ring rather than the furan ring of 2 and 3.

Determination of Perilla ketone in Perilla Herb by capillary gas chromatography/mass spectrometry.

Perilla ketone (PK), a potent lung toxin, in Perilla Herb was determined by capillary gas chromatography/mass spectrometory (capillary GC-MS). Without any cleanup, PK in ethyl acetate extract from a Perilla Herb sample was well separated by using a middle polar fused silica column (DB-17), and for the identification, mass chromatography monitoring m/z 166 from the molecular ion and m/z 110 and 95 from the fragment ions was carried out under an E.I. condition. Selective ion monitoring (SIM) of the both McLafferty rearrangement peaks, m/z 110 from PK and 112 from menthone added as an internal standard, allows sensitive and accurate quantification. The calibration curve was rectilinear in the range from 0.005 ng to 10 ng with the identification limit of 0.001 ng. The average recovery was 97.6% for PK added to Perilla Herb at the level of 300μg/500 mg. By this method, crude drugs on the market were analyzed : PK detected from 9 out of 25 samples (36%), and the amounts of PK ranged from 1.1 to 119.9 mg/100 g. It turned out that the PK doses taken in a day are less than 1/104-1/103 levels of LD50 to the mice.

Genetic control of perillene accumulation in Perilla frutescens

To study the genetic control of perillene formation in the glandular trichomes of Perilla frutescens, a novel chemotype (PL) containing perillene as a major component of the volatile oil was crossed with plants of the perillaketone (PK) and elsholtziaketone (EK) types. Analysis of F 1 and F 2 progenies showed that perillene is accumulated in plants lacking a dominant gene J which presumably controls the oxidative conversion of perillene into egonmaketone.

Determination of Final Steps in Biosyntheses of Essential Oil Components inPerilla frutescens

Biosynthetic pathways of the essential oil components in PERILLA FRUTESCENS were examined by tracer experiments using [ (14)C]-labeled sucrose on two chemotypes: perillaketone (PK) and phenylpropanoid (PP-EM) types. The results of the experiments indicated that perillaketone is not converted from isoegomaketone but is synthesized directly from the hypothetical precursor egomaketone. On the other hand, it was shown that elemicin is not synthesized via myristicin but from the possible common precursor, methyleugenol, in the plant having the dominant gene E. These results validate the hypothetical pathways proposed by Hegnauer and Fujita.

A novel use of Intralipid for the patenterai delivery of perilla ketone (NSC-348407), an investigational cytotoxic drug with a high affinity for plastic

Simulated i.v. infusions of perilla ketone, a highly lipophilic investigational cytotoxic agent, in 5% dextrose injection (D5W) through various types of i.v. administration sets resulted in considerable loss of the drug due to uptake by the plastic. Ipomeanol, a structurally similar cytotoxic agent with reduced lipophilicity, where a methyl group was replaced by a hydroxyl group, was not subject to uptake as predicted by the differences in the partitioning behavior of the two compounds. Uptake of perilla ketone by Polyvinylchloride -based sets was much greater than by polyethylene- or polyolefine-based sets. This phenomenon was completely prevented by incorporating perilla ketone into a commercially available fat emulsion, Intralipid.

Perilla ketone: a model of increased pulmonary microvascular permeability pulmonary edema in sheep.

A model of increased microvascular permeability pulmonary edema was developed in chronically instrumented unanesthetized sheep using perilla ketone (PK). PK did not cause changes in pulmonary hemodynamics but did cause marked increases in the flow of protein-rich lung lymph. The changes in lung lymph flow were accompanied by radiographic evidence of both interstitial and alveolar pulmonary edema as well as hypoxemia. PK did not cause acute changes in lung mechanics. Dynamic compliance of the lungs and FRC decreased later, concomitant with the changes in lung lymph flow, radiographic evidence for pulmonary edema, and hypoxemia. Resistance to air flow across the lungs and specific conductance did not change significantly after PK infusion. The severity of the radiographic evidence for pulmonary edema observed after PK correlated with the severity of the concomitant hypoxemia and changes in dynamic compliance of the lungs. PK did not cause increases in the concentrations of cyclooxygenase products of arachidonic acid in lung lymph or plasma or changes in blood leukocyte counts. We conclude that PK causes increased lung microvascular permeability pulmonary edema without acute changes in pulmonary hemodynamics. This model permits study of the pathophysiologic aspects of increased lung microvascular permeability without the concomitant functional alterations that complicate most other experimental models of diffuse lung injury.

The Essential Oil ofPerilla ocimoides:A Rich Source of Rosefuran

The essential oil of a strain of PERILLA OCIMOIDES from Bangladesh, cultivated at Lucknow, after GC-MS investigations afforded rosefuran ( 1) as the major constituent (58%) along with 17 others including beta-caryophyllene, perilla ketone ( 2), perillene, alpha-cedrene, germacrene-D, and isobis-abolene.

Genetic control of the chemical composition of volatile oils in Perilla frutescens

In order to clarify the genetic basis for chemical variations of the volatile oil components in Perilla frutescens, the F1 and F2 progenies of the artificial hybrids between the following different chemotypes have been examined individually for chemical compositions of the volatile oils extracted from the leaves: PA (perillaildehyde), EK (elsholtziaketone), PK (perillaketone) and PP (phenylpropanoid) types. The results of the genetic experiments have clearly demonstrated that the chemical composition is controlled by a series of multiple alleles (G1 G2, g) and an independent pair of alleles (H, h). The presence of either G1 or G2 is essential for initiating the biosynthesis of any monoterpenoids in Perilla plants. However, G1 and G2 function differently in determining the kinds of monoterpenes to be produced; G1 that produces the EK type is dominant over G2 that produces the PK type, while the homozygous recessive (gg) plants produce characteristic phenylpropanoids (myristicin, dillapiol, elemicin) in place of the monoterpenoids. In the presence of G1 or G2, plants homozygous for the dominant allele H (G-HH) produce volatile oil of the PA type, whereas those heterozygous for H (G-Hh) accumulate a large amount of l-limonene which is considered to be an intermediate metabolite in the biosynthesis of perillaldehyde. The roles of these genes are discussed in relation to the biosynthetic pathways.

Species susceptibility to the pulmonary toxicity of 3-furyl isoamyl ketone (perilla ketone): in vivo support for involvement of the lung monooxygenase system.

To explore a possible relationship between metabolism and lethality, the acute toxicity of naturally occurring perilla ketone (PK), 1-(3-furyl)-4-methyl-pentan-1-one, was examined in the uninduced mouse, hamster, rabbit, dog and pig. The LD50 (+/- SE), determined using intraperitoneal (ip) injection, for the mouse and hamster were low at 5.0 +/- .3 and 13.7 +/- .9 mg/kg, respectively. The rabbit died from an ip dosage of near 14 mg/kg and estimated ip LD50 dosages were quite high for the dog and pig, being 106 +/- 25 mg/kg and over 158 mg/kg, respectively. Dogs and the pig that died from ip injections of PK displayed varying degrees of midzonal and centrilobular liver damage and dogs also had elevated serum alkaline phosphatase and glutamic-pyruvic transaminase activities. In contrast, rodents and rabbits display only pulmonary toxicity from this agent. Cytochromes P-450 and b5 concentrations and NADPH-cytochrome c reductase activity were determined for the lung, liver and kidney of mice, hamsters, rabbits, dogs, swine, sheep and cattle. High correlation between lethality and enzyme concentration further supports the hypothesis that enzymatic bioactivation of PK is required for toxicity in all species.

Perilla ketone toxicity: a chemical model for the study of equine restrictive lung disease.

Perilla ketone was assessed for its usefulness as a model of equine restrictive pulmonary disease. Three ponies were given 18 mg/kg bodyweight synthetic perilla ketone in dimethyl-sulphoxide. Within 24 h of administration, respiratory rate, peak inspiratory and expiratory flow rates and minute volume were increased. By 48 h there was a significant decrease in tidal volume, and blood pH and base excess were also decreased but not outside normal limits. At necropsy there was congestion and oedema of the lungs. Histologically there was diffuse alveolar injury but no evidence of significant obstruction in bronchial or bronchiolar lumina. It is assumed that perilla ketone toxicity in ponies produces a restrictive disease without a significant obstructive component.

ChemInform Abstract: A CONVENIENT METHOD FOR THE PREPARATION OF 3‐ACYLFURANS. A NEW SYNTHESIS OF PERILLA KETONE

Chemischer InformationsdienstVolume 11, Issue 6 Heterocyclic Compounds ChemInform Abstract: A CONVENIENT METHOD FOR THE PREPARATION OF 3-ACYLFURANS. A NEW SYNTHESIS OF PERILLA KETONE K. INOMATA, K. INOMATASearch for more papers by this authorM. SUMITA, M. SUMITASearch for more papers by this authorH. KOTAKE, H. KOTAKESearch for more papers by this author K. INOMATA, K. INOMATASearch for more papers by this authorM. SUMITA, M. SUMITASearch for more papers by this authorH. KOTAKE, H. KOTAKESearch for more papers by this author First published: February 12, 1980 https://doi.org/10.1002/chin.198006230AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume11, Issue6February 12, 1980 RelatedInformation

A CONVENIENT METHOD FOR THE PREPARATION OF 3-ACYLFURANS. A NEW SYNTHESIS OF PERILLA KETONE

Abstract It was found that 3-(phenylthio)propanal ethylene acetal (IV) is a useful starting material for the preparation of 3-acylfurans. Some 3-acylfurans, including perilla ketone [3-(4-methylpentanoyl)furan], were prepared by the use of IV from an aziridide or aldehydes.

Perilla ketone: a potent lung toxin from the mint plant, Perilla frutescens Britton.

Perilla ketone, from the essential oil of Perilla frutescens, is a potent pulmonary edemagenic agent for laboratory animals and livestock. This finding would account for reported effects of the plant on grazing cattle. The use of perilla in oriental foods and medicinal preparations suggests possible hazards to human health as well.

STUDIES ON THE FOLIUM PERILLAE. II. ON ISOEGOMAKETONE

Essential oil of Perilla frutescens BRITTON var. crispa DECCAISNE f. discolor MAKINO contains two principle constituents. One is perilla ketone and the other is a new β-furyl ketone. The latter was separated by rectification and fractional gas chromatography. Through infrared and nuclear magnetic resonance spectra, and ozone oxidation, this substance was found to be isoegomaketone 1-(3-furyl)-4-methyl-2-penten-1-one.