Determination of camphor in spirit of camphor extraction with dichlorethyl ether.
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Alcoholic Beverages↗
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[Amine derivatives from 3-carboethoxy-(plus)camphor and from 3-cyano-(plus)camphor].
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Amines↗
[Aminoether derivatives of 3-hydroxymethylene-(plus)camphor and 3-isonitroso-(plus)camphor].
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Amines↗
[Comparative study "in vitro" of the long range action of camphorated paramonochlorophenol, chrystalized thymol, alcohol solution of thymol and camphorated thymol solution].
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Anti-Infective Agents↗
Camphor Poisoning: an evidence-based practice guideline for out-of-hospital management.
A review of national poison center data from 1990 through 2003 showed approximately 10,000 annual ingestion exposures to camphor-containing products. A guideline that determines the threshold dose for emergency department referral and need for pre-hospital decontamination could potentially avoid unnecessary emergency department visits, reduce health care costs, optimize patient outcome, and reduce life disruption for patients and caregivers. An evidence-based expert consensus process was used to create the guideline. Relevant articles were abstracted by a trained physician researcher. The first draft of the guideline was created by the primary author. The entire panel discussed and refined the guideline before distribution to secondary reviewers for comment. The panel then made changes based on the secondary review comments. The objective of this guideline is to assist poison center personnel in the appropriate out-of-hospital triage and initial management of patients with suspected exposures to camphor-containing products by 1) describing the manner in which an exposure to camphor might be managed, 2) identifying the key decision elements in managing cases of camphor exposure, 3) providing clear and practical recommendations that reflect the current state of knowledge, and 4) identifying needs for research. This guideline applies to camphor exposure alone. Co-ingestion of additional substances, such as in commercial products of camphor combined with other ingredients, could require different referral and management recommendations depending on the combined toxicities of the substances. This guideline is based on an assessment of current scientific and clinical information. The expert consensus panel recognizes that specific patient care decisions may be at variance with this guideline, and are the prerogative of the patient and the health professionals providing care, considering all of the circumstances involved. This guideline does not substitute for clinical judgment. Recommendations are in chronological order of likely clinical use. The grade of recommendation is in parentheses. 1) Patients with stated or suspected self-harm or who are the recipients of malicious administration of a camphor-containing product should be referred to an emergency department immediately, regardless of the amount ingested (Grade D). 2) Patients who have ingested more than 30 mg/kg of a camphor-containing product or who are exhibiting symptoms of moderate to severe toxicity (e.g., convulsions, lethargy, ataxia, severe nausea and vomiting) by any route of exposure should be referred to an emergency department for observation and treatment (Grade D). 3) Patients exhibiting convulsions following a camphor exposure should be transported to an emergency department by pre-hospital emergency medical care providers (Grade D). A benzodiazepine should be used to control convulsions (Grade C). 4) Patients who have been exposed to a camphor product and who remain asymptomatic after 4 hours can be safely observed at home (Grade C). 5) Induction of emesis with ipecac syrup should not be performed in patients who have ingested camphor products (Grade C). 6) Activated charcoal administration should not be used for the ingestion of camphor products. However, it could be considered if there are other ingredients in the product that are effectively adsorbed by activated charcoal or if other substances have been co-ingested. (Grade C). 7) For asymptomatic patients with topical exposures to camphor products, the skin should be thoroughly washed with soap and water and the patient can be observed at home for development of symptoms (Grade C). 8) For patients with topical splash exposures of camphor to the eye(s), the eye(s) should be irrigated in accordance with usual poison center procedures and that referral take place based on the presence and severity of symptoms (Grade D). 9) Patients with camphor inhalation exposures should be moved to a fresh air environment and referred for medical care based on the presence and severity of symptoms. It is unlikely that symptoms will progress once the patient is removed from the exposure environment (Grade D).
Camphor↗
Camphor activates and strongly desensitizes the transient receptor potential vanilloid subtype 1 channel in a vanilloid-independent mechanism.
Camphor is a naturally occurring compound that is used as a major active ingredient of balms and liniments supplied as topical analgesics. Despite its long history of common medical use, the underlying molecular mechanism of camphor action is not understood. Capsaicin and menthol, two other topically applied agents widely used for similar purposes, are known to excite and desensitize sensory nerves by acting on two members of transient receptor potential (TRP) channel superfamily: heat-sensitive TRP vanilloid subtype 1 (TRPV1) and cold-sensitive TRP channel M8, respectively. Camphor has recently been shown to activate TRPV3, and here we show that camphor also activates heterologously expressed TRPV1, requiring higher concentrations than capsaicin. Activation was enhanced by phospholipase C-coupled receptor stimulation mimicking inflamed conditions. Similar camphor-activated TRPV1-like currents were observed in isolated rat DRG neurons and were strongly potentiated after activation of protein kinase C with phorbol-12-myristate-13-acetate. Camphor activation of rat TRPV1 was mediated by distinct channel regions from capsaicin, as indicated by camphor activation in the presence of the competitive inhibitor capsazepine and in a capsaicin-insensitive point mutant. Camphor did not activate the capsaicin-insensitive chicken TRPV1. TRPV1 desensitization is believed to contribute to the analgesic actions of capsaicin. We found that, although camphor activates TRPV1 less effectively, camphor application desensitized TRPV1 more rapidly and completely than capsaicin. Conversely, TRPV3 current sensitized after repeated camphor applications, which is inconsistent with the analgesic role of camphor. We also found that camphor inhibited several other related TRP channels, including ankyrin-repeat TRP 1 (TRPA1). The camphor-induced desensitization of TRPV1 and block of TRPA1 may underlie the analgesic effects of camphor.
Animals↗
Mutations of glutamate-84 at the putative potassium-binding site affect camphor binding and oxidation by cytochrome p450cam.
Cytochrome P450cam (CYP101) from Pseudomonas putida is unusual among P450 enzymes in that it exhibits co-operative binding between the substrate camphor and a potassium ion. This behaviour has been investigated by mutagenesis of Glu84, a surface residue which forms part of the cation-binding site. Substitutions that neutralize or reverse the charge of this side chain are shown to disrupt the co-operativity of potassium and camphor binding by P450cam, and also to influence the catalytic activity. In particular, replacement of Glu84 by positively charged residues such as lysine results in increased high-spin haem fractions and camphor turnover activities in the absence of potassium, along with decreased camphor dissociation constants. However, in the presence of potassium the camphor dissociation constants of these mutants are significantly increased compared with the wild-type, although the camphor turnover activities remain marginally higher. In contrast, substitution by aspartate results in tighter binding of both potassium and camphor, but has little effect on the enzymatic activity. In all cases the reaction remains essentially 100% coupled and gives 5-exo-hydroxycamphor as the only product. These results suggest that an anionic side chain at the 84 position is crucial for the co-operativity of camphor and cation binding, and that the physiological role for potassium binding by cytochrome P450cam is to promote camphor binding even at the expense of turnover rate, thus allowing the organism to utilize low environmental concentrations of this substrate for growth.
Amino Acid Substitution↗
A sensitive liquid chromatographic procedure for the analysis of camphor in equine urine and plasma.
A sensitive method was required to analyze low levels of camphor in equine urine and plasma. Camphorated oil (20% w/w camphor) was administered topically (6 g) and intratracheally (1 g) to standardbred mares. The drug was extracted from urine and plasma by diethyl ether and analyzed as its 2,4-dinitrophenylhydrazone derivative by reverse phase HPLC with UV detection. The UV detector was set at 368.5 nm and the samples were eluted from the C18 column by 82% acetonitrile in water. The detection limit achieved was about 10 ng/mL urine and about 20 ng/mL plasma. After topical administration, only trace amounts of camphor were found in urine, whereas in plasma detectable quantities appeared from 20 min to 12 hrs post-administration. After intratracheal administration, camphor appeared immediately in both urine and plasma and occurred in higher concentrations. The concentrations of camphor ranged from 11.4 to 21.6 ng/mL urine during 2 hrs post-administration and from 46.7 to 1650 ng/mL plasma during 1 hr. All traces of camphor disappeared from urine after 4 hrs and from plasma after 12 hrs. A GC/MS analysis of hydrolyzed urine extracts indicated two metabolites of camphor: trans-isoketopinic acid and an as yet uncharacterized hydroxycamphor.
Animals↗
Inhibition of oxidative metabolism in Escherichia coli by d-camphor and restoration of oxidase activity by quinones.
Oxidative metabolism in whole cells of Escherichia coli strain 82/r was inhibited by d-camphor when glucose, pyruvate, or succinate was used as substrate. Inhibition was not due to lower surface tension in d-camphor-treated cell suspensions nor was it a function of cell permeability. Succinic, lactic, and NADH-oxidase activities were inhibited in alumina powder cell-free extracts (80 mug of protein/ml) by d-camphor (1100 mug/ml). NADH: and succinic: DCPIP oxidoreductase enzymes were unaffected by d-camphor. Menadione (vitamin K3) restored succinic, lactic, and NADH-oxidase activities in d-camphor-inhibited cell-free extracts. Concentrations of menadione used to restore succinic and NADH oxidase activities were not stimulatory in non-camphor-treated extracts. Succinic oxidase activity in d-camphor-inhibited cell-free extracts was also restored by ubiquinone (Q6) but not by vitamin K1. These results are interpreted to indicate that d-camphor may affect quinone function in E. coli.
Camphor↗
In vivo evaluation of the adsorptive capacity of activated charcoal for camphor.
Camphor, a cyclic terpene, is the toxic ingredient in many over-the-counter (OTC) products. Early seizure activity due to camphor ingestion often contraindicates the use of traditional decontamination therapies in favor of oral activated charcoal use. No research data supports the affinity of activated charcoal for camphor. This study was conducted to evaluate the effectiveness of activated charcoal in preventing camphor absorption in a rat model. Camphor 40% in cottonseed oil (1 g/kg) was administered to 100 male Sprague-Dawley rats via oral gavage. Aqueous activated charcoal suspension (2 g/kg) was administered to the study group of 50 rats. Serum camphor concentrations were determined by gas chromatography at defined intervals over 10 h. No mortality occurred in either the control or activated charcoal-treated group. Area-under-the-curve bioavailability comparisons of each group revealed no significant differences (activated charcoal 421 micrograms x h/ml vs camphor 409 micrograms x h/ml). The absorption rate constants (Ka) and T 1/2 and elimination rate constants (Ke) and T 1/2 of each group were nearly identical and similar to those reported for humans. These preliminary data indicate the need for careful evaluation of the efficacy of oral activated charcoal administration as the sole means of preventing the absorption of camphor.
Adsorption↗
Structural studies of an eukaryotic cambialistic superoxide dismutase purified from the mature seeds of camphor tree.
An iron-superoxide dismutase (SOD) was purified and characterized from the mature seeds of camphor tree (Cinnamomum camphora). The ultraviolet and visible absorption spectra of camphor Fe-SOD showed patterns typical of cambialistic Fe-SODs. The inductively coupled plasma assay indicated that there was 0.5-1 atom of Fe(2+) per camphor Fe-SOD subunit. The cDNA of camphor Fe-SOD, including the coding region and the 3' noncoding region, was obtained by reverse transcription polymerase chain reaction using the total RNA from immature seeds of C. camphora as template and then sequenced. The complete amino acid sequence of camphor Fe-SOD was deduced from the cDNA sequence. The correctness of the amino acid sequence was confirmed by directly sequencing five peptide fragments of the enzyme. The molecular mass calculated for the camphor Fe-SOD subunit from its 204 amino acid residues was 22,930.6 Da, The cDNA of camphor Fe-SOD was cloned into the expression vector PMFT7-5 and then expressed in Escherichia coli strain BL21. The reconstructed Fe- or Mn-SOD was purified to homogeneity through column chromatography. Activity of the Fe- or Mn-SOD was found to be almost equal to that of natural camphor Fe-SOD, which is the first cambialistic SOD isolated from eukaryotic cells.
Base Sequence↗
Catabolism of camphor in tissue cultures and leaf disks of common sage (Salvia officinalis).
(+)-Camphor constitutes nearly 30% of the monoterpenes accumulated in the leaves of common sage (Salvia officinalis), and as the plant approaches maturity the content of this monoterpene ketone decreases by roughly half. Although the ability to catabolize camphor has been demonstrated previously in sage leaf disks, tissue cultures proved to be a more suitable system for examining the responsible degradative pathway. Cell suspension cultures were shown to convert (+)-[3-3H2]camphor, in sequence, to 6-hydroxycamphor, 6-oxocamphor, alpha-campholonic acid, and 2-hydroxy-alpha-campholonic acid, and each intermediate of the pathway was identified by chromatographic and spectroscopic means. This oxidative ring opening sequence resembles the pathway for camphor degradation by the soil diphtheroid, Mycobacterium rhodochrous, that ultimately leads to isoketocamphoric as the last defined metabolite that contains all 10 carbons of the original bicyclic nucleus. Studies with both cell cultures and leaf disks also demonstrated that the catabolism of camphor via 1,2-campholide, a metabolite in sage leaves previously described, was a minor degradative pathway. The first step in the metabolism of camphor was demonstrated in cell-free extracts of the cultured sage cells, and several lines of evidence indicated that this microsomal (+)-camphor-6-exo-hydroxylase is a cytochrome P-450-dependent monooxygenase.
Camphor↗
Toxicokinetics and biotransformation of 3-(4-methylbenzylidene)camphor in rats after oral administration.
3-(4-Methylbenzylidene)camphor (4-MBC) is an UV-filter frequently used in sunscreens and cosmetics. Equivocal findings in some screening tests for hormonal activity initiated a discussion on a possible weak estrogenicity of 4-MBC. In this study, the toxicokinetics and biotransformation of 4-MBC were characterized in rats after oral administration. Male and female Sprague-Dawley rats (n = 3 per group) were administered single oral doses of 25 or 250 mg/kg bw of 4-MBC in corn oil. Metabolites formed were characterized and the kinetics of elimination for 4-MBC and its metabolites from blood and with urine were determined. Metabolites of 4-MBC were characterized by (1)H NMR and LC-MS/MS as 3-(4-carboxybenzylidene)camphor and as four isomers of 3-(4-carboxybenzylidene)hydroxycamphor containing the hydroxyl group located in the camphor ring system with 3-(4-carboxybenzylidene)-6-hydroxycamphor as the major metabolite. After oral administration of 4-MBC, only very low concentrations of 4-MBC were present in blood and the peak concentrations of 3-(4-carboxybenzylidene)camphor were approximately 500-fold above those of 4-MBC; blood concentrations of 3-(4-carboxybenzylidene)-6-hydroxycamphor were below the limit of detection. Blood concentration of 4-MBC and 3-(4-carboxybenzylidene)camphor peaked within 10 h after 4-MBC administration and then decreased with half-lives of approximately 15 h. No major differences in peak blood levels between male and female rats were seen. In urine, one isomer of 3-(4-carboxybenzylidene)hydroxycamphor was the predominant metabolite [3-(4-carboxybenzylidene)-6-hydroxycamphor], the other isomers and 3-(4-carboxybenzylidene)camphor were only minor metabolites excreted with urine. However, urinary excretion of 4-MBC-metabolites represents only a minor pathway of elimination for 4-MBC, since most of the applied dose was recovered in feces as 3-(4-carboxybenzylidene)camphor and, to a smaller extent, as 3-(4-carboxybenzylidene)-6-hydroxycamphor. Glucuronides of both metabolites were also present in feces, but partly decomposed during sample workup and were thus not quantified. The results show that absorbed 4-MBC undergoes extensive first-pass biotransformation in rat liver resulting in very low blood levels of the parent 4-MBC. Enterohepatic circulation of glucuronides derived from the two major 4-MBC metabolites may explain the slow excretion of 4-MBC metabolites with urine and the small percentage of the administered doses recovered in urine.
Administration, Oral↗
Noncompetitive inhibition by camphor of nicotinic acetylcholine receptors.
The effect of camphor, a monoterpenoid, on catecholamine secretion was investigated in bovine adrenal chromaffin cells. Camphor inhibited [3H]norepinephrine ([3H]NE) secretion induced by a nicotinic acetylcholine receptor (nAChR) agonist, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), with a half-maximal inhibitory concentration (IC50) of 70 +/- 12 microM. In addition, camphor inhibited the rise in cytosolic calcium ([Ca2+]i) and sodium ([Na+]i) induced by DMPP with IC50 values of 88 +/- 32 and 19 +/- 2 microM, respectively, suggesting that the activity of nAChRs is also inhibited by camphor. On the other hand, binding of [3H]nicotine to nAChRs was not affected by camphor. [Ca2+]i increases induced by high K+, veratridine, and bradykinin were not affected by camphor. The data suggest that camphor specifically inhibits catecholamine secretion by blocking nAChRs without affecting agonist binding.
Animals↗
The chemical UV-filter 3-benzylidene camphor causes an oestrogenic effect in an in vivo fish assay.
Chemical UV-filters are used in sun protection products and various kinds of cosmetics. The lipophilic chemical UV-filter 3-benzylidene camphor was investigated for its capability to cause vitellogenin induction, possibly via oestrogen receptor binding, in a well-established in vivo fish assay (juvenile rainbow trout, Oncorhynchus mykiss, vitellogenin ELISA). A clear relationship was demonstrated between the dose of injected 3-benzylidene camphor and the concentration of plasma vitellogenin with a 105-times induction from 68 mg 3-benzylidene camphor /kg/injection and above compared to the control vitellogenin level. The relationship between the injected dose of 3-benzylidene camphor and the percent of responding fish (vitellogenin) was evaluated by logistic regression analysis and effective dose-values (ED-values) were determined. ED10, ED50 and ED90 of 3-benzylidene camphor after 6 days (2 injections) were 6.4, 16 and 26 mg/kg/ injection, respectively. These ED-values place 3-benzylidene camphor among the more potent xenooestrogens discovered to date and necessitates investigations on the distribution, concentration, persistence and bioaccumulation of 3-benzylidene camphor and other UV-filters in nature.
Animals↗
Induction and Characterization of a Cytochrome P-450-Dependent Camphor Hydroxylase in Tissue Cultures of Common Sage (Salvia officinalis).
(+)-Camphor, a major monoterpene of the essential oil of common sage (Salvia officinalis), is catabolized in senescent tissue, and the pathway for the breakdown of this bicyclic ketone has been previously elucidated in sage cell-suspension cultures. In the initial step of catabolism, camphor is oxidized to 6-exo-hydroxycamphor, and the corresponding NADPH- and O2-dependent hydroxylase activity was demonstrated in microsomal preparations of sage cells. Several well-established inhibitors of cytochrome P-450-dependent reactions, including cytochrome c, clotrimazole, and CO, inhibited the hydroxylation of camphor, and CO-dependent inhibition was partially reversed by blue light. Upon treatment of sage suspension cultures with 30 mM MnCl2, camphor-6-hydroxylase activity was induced up to 7-fold. A polypeptide with estimated molecular mass of 58 kD from sage microsomal membranes exhibited antigenic cross-reactivity in western blot experiments with two heterologous polyclonal antibodies raised against cytochrome P-450 camphor-5-exo-hydroxylase from Pseudomonas putida and cytochrome P-450 limonene-6S-hydroxylase from spearmint (Mentha spicata). Dot blotting indicated that the concentration of this polypeptide increased with camphor hydroxylase activity in microsomes of Mn2+-induced sage cells. These results suggest that camphor-6-exo-hydroxylase from sage is a microsomal cytochrome P-450 monooxygenase that may share common properties and epitopes with bacterial and other plant monoterpene hydroxylases.
Journal Article↗
Crystal structure of cytochrome P-450cam complexed with the (1S)-camphor enantiomer.
The crystal structure of cytochrome P-450cam complexed with the enantiomer (1S)-camphor has been solved to 1.8 angstroms resolution and compared with the structure of the (1R)-camphor P-450cam complex. The overall protein structure is the same for both enantiomer complexes. However, the orientation of the substrates in the heme pocket differs. In contrast to (1R)-camphor, the (1S)-enantiomer binds in at least two orientations. The major binding mode of (1S)-camphor resembles the one of the (1R)-enantiomer in that there is a hydrogen bond between Tyr-96 and the quinone group of camphor, and the 10-methyl group points towards the I-helix. The binding differs in that C-5 is not at a position suitable for hydroxylation. In the other orientation (1S)-camphor is not hydrogen bonded, but C-5 is located suitably for hydroxylation.
Camphor↗
Multicopy molecular dynamics simulations suggest how to reconcile crystallographic and product formation data for camphor enantiomers bound to cytochrome P-450cam.
Multiple ligand binding modes are possible in many enzyme active sites; their presence in cytochrome P450cam (P450cam) is evident from crystallographic studies of the binding of thiocamphor and phenylimidazoles. Here, we use multicopy molecular dynamics simulations to compare the binding modes of (1R)- and (1S)-camphor in the active site of P450cam. Simulations with (1R)-camphor, the natural substrate, serve to calibrate our protocol: 19 out of 20 copies of (1R)-camphor converged to coordinates very close to those observed for (1R)-camphor in its crystallographic complex with P450cam during the simulations. Simulations with the (1S)-camphor enantiomer showed greater mobility of the substrate, consistent with spectroscopic data, and resulted in 3 major binding modes. One of these is similar to the major conformation (of the two conformations assigned) in a recently determined crystal structure, but this conformation is not correctly oriented for regiospecific hydroxylation at C-5. The simulations, however, provide evidence for reorientation of (1S)-camphor upon formation of the reactive Fe-O intermediate to an orientation suitable for hydroxylation. The simulations thus permit rationalisation of the apparent inconsistency between the crystal structure and the reaction products.
Binding Sites↗