Cedrene and cedrol

An olfactory receptor in fat cells? Olfactory Receptor Family 10 Subfamily J Member 5 (OR10J5) is a typically G protein coupled receptor that signals through Gas pathways. GeneCards.org has perhaps the best expression data for OR10J5, the human version of Mouse olfactory receptor 23 MOR23. Tissue expression in the feature image is Illumina mRNA sequencing data in units of “fragments per kilobase per exon per million fragments mapped.” The scale goes up to 1000.

A terpene binding to an olfactory receptor in our fat?

A study out of South Korea examined the tissue deposition of α-cedrene in rats as a preliminary of this drug being evaluated as an anti obesity treatment. [1] α-Cedrene was administered intravenously (10 and 20 mg/kg) and orally (50 and 100 mg/kg) to female and male Sprague-Dawley rats. Only about half to 80% of the α-cedrene was absorbed by the oral route with preferential distribution to fatty tissues. [1] A mono-hydroxylated metabolite was identified as a preliminary metabolite in rat plasma. [1]

Taesun Park’sgroup used a mouse fibroblast 3T3 L1 cell line. These cell lines can be usdifferentiated into adipocytes by hormone treatment. In the introduction of this study the authors cited previous work showing that α-cedrene protects rats from weight gain resulting from a high fat diet. [2] Dr Park’s work with fatty liver disease if featured on the camphene page.

• Preadipocytes were treated with 100 μM α-cedrene ± silencing RNA (siRNA) that prevents MOR23 mRNA transcripts from being translated into protein. MOR23 siRNA slightly decreased oil red stainable fat droplets and inhibited the ability of 100 μM α-cedrene to inhibit that increase in fat. cAMP inversely followed this increase in fat. [2]
• The Park group found that α-cedrene increased protein levels of adenylyl clause 3, the Cα subunit of protein kinase A, and the fraction of phosphorylated (activated) AMP regulated Protein Kinase. These increases were abolished by MOR23 siRNA.[2]
• Dr Park’s group used PCR to detect changes in the mRNA transcripts of many genes involved in fatty acid metabolism and mitochondrial respiration.
• Back to the protein assays, Dr Park’s group showed an increase the the fraction of phosphorylated (activated) cAMP Response Element Binding protein (CREB)
• This increase is consistent in the increase in mRNA transcripts for mitochondia proteins that include the Uncoupler protein 1 that turns mitochondria into fat burning, heat generating factories.

The Oxygen Consumption Rate (OCR) was measured two days after the siRNA transfection. The yellow arrows drawn on the electron transport chain diagram indicate protein transcript increases, for example COX4 in complex IV. FCCP has the same action as UCP1 in transporting H⁺ across the inner membrane uncoupled to ATP generation. It should be added that siRNA was transfected 48 prior to adipogenesis with

transition

The Park group has studied α-cedrene in rat models of fatty liver disease [4] and skeletal muscle sacropenia. [5] What about the metabolic alcohol biproduct [1] cedrol ? What does it do?

Cedrol

Asians tend to be into the therapeutic benefits in breathing in nature. Umeno and coworkers in Japan used totally laryngectomized subjects so as to have a means of administering cedrol vapor and bypassing olfactory receptors in the nose that might be contributing to the relaxation. [6] The vitals were measured real time. As one might imagine, parameters were “bouncing around.” The variability was divided into low frequency and high frequency sine waves. Cedrol tended to stabilize the real time “bouncing around” of cardiovascular variability. The argument was presented for an autonomic response via pulmonary C-fibers. [6]

• systolic blood pressure, decrease
• diastolic blood pressure, decrease
• heart rate, no change
• respiration rate, no change

C-fibers make a certain amount of sense. Many terpenes featured on this site bind to TrpA1 and/or TrpV1 channels. Agonists of both, allyl isothiocyante and capsaicin, were found to synergize to activate pulmonary C-fibers with intravenous injections. [7] These authors tested chemical stimulants of C-fibers receptors: 5-HT3,P2X2 and P2X3, adenosine A1. [7] No mention was made of OR10J5/MOR23.

Cedarwood oil has both

A toxicology study has examined a complex mixture of terpenes from a Virgina variety of cedarwood oil[8] The top five components are

1. 27.01% α-cedrene,
2. 21.83% cedrol
3. 19.64% thujopsene
4. 6.05% β-cedrene
5. 0.96% cuparene

Most consumers encounter cedarwood oil via the dermal route of exposure through skin and hair care products. Therefore toxicology studies focused on ethanol diluted mixtures of cedar wood at 6.25%, 12.5%, 25%, or 50% (with 95% ethanol as the vehicle and 100% (neat) cedarwood oil. [8] These applied concentrations corresponded to approximately 31.25 to 500 mg cedarwood oil/kg body weight in the rat and 125 to 2,000 mg/kg in the mouse. [8] To summarize a long study, notwithstanding the dermal site of application, the kidney was the major site of toxicity along with the and liver and other organs. [8] This study referenced another report of marked inhibition of chytochrome P450family member Cyp3A4 by cedrol. [9] According to the UniProt database Cyp3A4 catalyzes the hydroxylation/inactivation of steroid hormones, retinoids, and cholesterol. Cedrol, β-cedrene, and thujopsene were found to be potent competitive inhibitors of CYP2B6. [9] Cyp2B6 is responsible for metabolizing endocannabinoids and steroids. Cyp2B6 introduces epoxide groups into pi bonds rather than hydroxyl groups introduced Cyp3A4. The Ki ‘s listed on UniProt are well below in vivo rodent studies. For this reason, Cyp3A4 and Cyp2B6 are being awarded the title of the cedrol target on this site. Interestingly, non of these P450s are expressed in large amounts in the kidney.These renal toxic effects were only observed in the really high concentrations of cedar wood oil. [8]

Does cedrol bind to OR10j5/MOR23? It would create an interesting story if it did. It would suggest some evolutionary purpose for having olfactory receptors scattered in some unknown amounts. There are some reports of cedrol interacting with other G protein coupled receptors in rodents that will not be discussed for now.

references

1. Kim TH, Yoo SD, Lee HS, Lee KM, Seok SH, Kim MG, Jung BH, Kim MG, Shin BS. (2015)In vivo absorption and disposition of α-cedrene, a sesquiterpene constituent of cedarwood oil, in female and male rats. Drug Metab Pharmacokinet. 2015 Apr;30(2):168-73.
2. Tong, T., Park, J., Moon, C., & Park, T. (2018). Regulation of Adipogenesis and Thermogenesis through Mouse Olfactory Receptor 23 Stimulated by α-Cedrene in 3T3-L1 Cells. Nutrients, 10(11), 1781. PMC free article
3. Tong T, Ryu SE, Min Y, de March CA, Bushdid C, Golebiowski J, Moon C, Park T. (2017) Olfactory receptor 10J5 responding to α-cedrene regulates hepatic steatosis via the cAMP-PKA pathway. Sci Rep. 2017 Aug 25;7(1):9471.
4. Tong T, Kim M, Park T. (2018) α-Cedrene, a Newly Identified Ligand of MOR23, Increases Skeletal Muscle Mass and Strength. Mol Nutr Food Res. 2018 Jun 14:e1800173.
5. Tong T, Kim M, Park T. (2018) α-Cedrene, a Newly Identified Ligand of MOR23, Increases Skeletal Muscle Mass and Strength. Mol Nutr Food Res. 2018 Jun 14:e1800173.
6. Umeno K, Hori E, Tsubota M, Shojaku H, Miwa T, Nagashima Y, Yada Y, Suzuki T, Ono T, Nishijo H. (2008) Effects of direct cedrol inhalation into the lower airway on autonomic nervous activity in totally laryngectomized subjects. Br J Clin Pharmacol. 2008 Feb;65(2):188-96. PMC free article
7. Lee, L. Y., Hsu, C. C., Lin, Y. J., Lin, R. L., & Khosravi, M. (2015). Interaction between TRPA1 and TRPV1: Synergy on pulmonary sensory nerves. Pulmonary pharmacology & therapeutics, 35, 87–93. PMC free article
8. National Toxicology Program. (2016) Toxicity studies of cedarwood oil (Virginia) administered dermally to F344/N rats and B6C3F1/N mice. Toxic Rep Ser. 2016 Nov;(86):NTP-TOX-86. free article
9. Jeong HU, Kwon SS, Kong TY, Kim JH, Lee HS. Inhibitory effects of cedrol, β-cedrene, and thujopsene on cytochrome P450 enzyme activities in human liver microsomes. J Toxicol Environ Health A. 2014;77(22-24):1522-32.