Carnosol

/CASE REPORTS/ A 56-year-old man, working in a food processing factory, developed contact dermatitis of his hands, forearms, and face after the introduction of a new herb extract (Rosmanox) made from the leaves of rosemary (Rosmarinus officinalis). He reacted to carnosol, the main constituent of Rosmanox. 226 controls were negative. To our knowledge, this is the 1st reported case of contact dermatitis from carnosol.

/GENOTOXICITY/ The radioprotective effects of carnosic acid (CA), carnosol (COL), and rosmarinic acid (RO) against chromosomal damage induced by gamma-rays, compared with those of L-ascorbic acid (AA) and the S-containing compound dimethyl sulfoxide (DMSO), were determined by use of the micronucleus test for antimutagenic activity, evaluating the reduction in the frequency of micronuclei (MN) in cytokinesis-blocked cells of human lymphocytes before and after gamma-ray irradiation. With treatment before gamma-irradiation, the most effective compounds were, in order, CA > RO > or = COL > AA > DMSO. The radioprotective effects (antimutagenic) with treatment after gamma-irradiation were lower, and the most effective compounds were CA and COL. RO and AA presented small radioprotective activity, and the sulfur-containing compound DMSO lacked gamma-ray radioprotection capacity. Therefore, CA and COL are the only compounds that showed a significant antimutagenic activity both before and after gamma-irradiation treatments...

/ALTERNATIVE and IN VITRO TESTS/ ... The mechanisms by which rosemary components block initiation of carcinogenesis by the procarcinogen benzo[a]pyrene (B[a]P) in human bronchial epithelial cells (BEAS-2B) /was studied/. Whole rosemary extract (6 ug/mL) or an equivalent concentration of its most potent antioxidant constituents, carnosol or carnosic acid, inhibited DNA adduct formation by 80% after 6 hr co-incubation with 1.5 uM B[a]P. Under similar conditions, cytochrome P450 (CYP) 1A1 mRNA expression was 50% lower in the presence of rosemary components, and CYP1A1 activity was inhibited 70-90%. The observed reduction of DNA adduct formation by rosemary components may mostly result from the inhibition of the activation of benzo[a]pyrene to its ultimate metabolites. Carnosol also affected expression of the phase II enzyme glutathione-S-transferase which is known to detoxify the proximate carcinogenic metabolite of B[a]P. Treatment of BEAS-2B cells with carnosol (1 microgram/ml) for 24 h resulted in a 3- to 4-fold induction of GST pi mRNA. Moreover, expression of a second important phase II enzyme, NAD(P)H: quinone reductase, was induced by carnosol in parallel with GST pi. Therefore, rosemary components have the potential to decrease activation and increase detoxification of an important human carcinogen, identifying them as promising candidates for chemopreventive programs.

/ALTERNATIVE and IN VITRO TESTS/ Carnosic acid (CA) and carnosol (CS) are phenolic diterpenes present in several labiate herbs like Rosmarinus officinalis (Rosemary) and Salvia officinalis (Sage). Extracts of these plants exhibit anti-inflammatory properties ... . CA and CS activate the peroxisome proliferator-activated receptor gamma, implying an anti-inflammatory potential on the level of gene regulation. ... Short-term effects of CA and CS on typical functions of human polymorphonuclear leukocytes (PMNL) /were/ ... (I), CA and CS inhibit the formation of pro-inflammatory leukotrienes in intact PMNL (IC(50)=15-20 uM [CA] and 7 uM [CS], respectively) as well as purified recombinant 5-lipoxygenase ..., IC(50)=1 uM [CA] and 0.1 uM [CS], respectively), (II) both CA and CS potently antagonize intracellular Ca(2+) mobilization induced by a chemotactic stimulus, and (III) CA and CS attenuate formation of reactive oxygen species and the secretion of human leukocyte elastase ... .. Together, /the/ findings provide a pharmacological basis for the anti-inflammatory properties reported for CS- and CA-containing extracts.

/ALTERNATIVE and IN VITRO TESTS/ The effects of 24 hr supplementation of Caco-2 cells with carnosic acid and carnosol, and their activities against 5 uM oleic acid hydroperoxide (OAHPx)-mediated oxidative stress, were investigated. At 24 hr of incubation, under nonstressed and stressed conditions, both compounds at 25, 50, and 100 uM supplement concentrations reduced catalase activity, whereas changes in glutathione peroxidase and superoxide dismutase activities varied depending upon the concentrations. Relative to control cultures, carnosic acid and carnosol reduced membrane damage by 40-50% when stressed by OAHPx. Carnosic acid and carnosol inhibited lipid peroxidation by 88-100% and 38-89%, respectively, under oxidative stress conditions. Both compounds significantly lowered DNA damage induced by OAHPx. Results of this study suggest that antioxidant activities of carnosic acid and carnosol could be partly due to their ability to increase or maintain glutathione peroxidase and superoxide dismutase activities.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ A methanol extract of the leaves of the plant Rosmarinus officinalis L. (rosemary) was evaluated for its effects on tumor initiation and promotion in mouse skin. Application of rosemary to mouse skin inhibited the covalent binding of benzo(a)pyrene [B(a)P] to epidermal DNA and inhibited tumor initiation by B(a)P and 7,12-dimethylbenz[a]anthracene (DMBA). Topical application of 20 nmol B(a)P to the backs of mice once weekly for 10 weeks, followed 1 week later by promotion with 15 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) twice weekly for 21 weeks, resulted in the formation of 7.1 tumors per mouse. In a parallel group of animals that were treated topically with 1.2 or 3.6 mg of rosemary 5 min prior to each application of B(a)P, the number of tumors per mouse was decreased by 54 or 64%, respectively. Application of rosemary to mouse skin also inhibited TPA-induced ornithine decarboxylase activity, TPA-induced inflammation, arachidonic acid-induced inflammation, TPA-induced hyperplasia, and TPA-induced tumor promotion. Mice initiated with 200 nmol DMBA and promoted with 5 nmol TPA twice weekly for 19 weeks developed an average of 17.2 skin tumors per mouse. Treatment of the DMBA-initiated mice with 0.4, 1.2, or 3.6 mg of rosemary together with 5 nmol TPA twice weekly for 19 weeks inhibited the number of TPA-induced skin tumors per mouse by 40, 68, or 99%, respectively. Topical application of carnosol or ursolic acid isolated from rosemary inhibited TPA-induced ear inflammation, ornithine decarboxylase activity, and tumor promotion. Topical application of 1, 3, or 10 umol carnosol together with 5 nmol TPA twice weekly for 20 weeks to the backs of mice previously initiated with DMBA inhibited the number of skin tumors per mouse by 38, 63, or 78%, respectively. Topical application of 0.1, 0.3, 1, or 2 umol ursolic acid together with 5 nmol TPA twice weekly for 20 weeks to DMBA-initiated mice inhibited the number of tumors per mouse by 45-61%.

/ALTERNATIVE and IN VITRO TESTS/ Laboratory experiments were conducted to study the antiplatelet activity of carnosol, a phenolic diterpene isolated from rosemary. Carnosol concentration-dependently inhibited washed rabbit platelet aggregation induced by collagen and arachidonic acid (AA), with IC50 values of 5.5+or-0.3 and 42.5+or-0.9 uM, respectively, while it failed to inhibit that induced by ADP and thrombin. Based on the inhibition of collagen-induced platelet aggregation, carnosol revealed blocking of collagen-mediated cytosolic calcium mobilization, serotonin secretion and AA liberation. However, contrary to the inhibition of AA-induced platelet aggregation, carnosol had no effect on AA-mediated TXA2 and PGD2 formation, indicating that carnosol may directly inhibit the TXA2 receptor, which was supported by the finding that carnosol potently inhibited U46619 (a TXA2 mimic)-induced platelet aggregation, with an IC50 value of 22.0+or-2.5 uM. In addition, the U46619-induced concentration-response curve shifted downward by the application of carnosol at 22 and 50 uM, indicating a typical non-competitive antagonism on the TXA2 receptor. Taken together, these results suggest that the antiplatelet activity of carnosol may be mediated by the inhibition of the TXA2 receptor and cytosolic calcium mobilization and that carnosol has a potential to be developed as a novel-antiplatelet agent.

/OTHER TOXICITY INFORMATION/ The peroxisome proliferator-activated receptors play a pivotal role in metazoan lipid and glucose homeostasis. Synthetic activators of PPARalpha (fibrates) and PPARgamma (glitazones) are therefore widely used for treatment of dislipidemia and diabetes, respectively. There is growing evidence for herbal compounds to influence nuclear receptor signalling e.g. the PPARs. /It was/ recently reported /that/ carnosic acid and carnosol ... /are/ activators of PPARgamma.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/