Δ9-Tetrahydrocannabinol and Its Major Metabolite Δ9-Tetrahydrocannabinol-11-oic Acid as 15-Lipoxygenase Inhibitors

Takeda, Shuso; Jiang, Rongrong; Aramaki, Hironori; Imoto, Masumi; Toda, Akihisa; Eyanagi, Reiko; Amamoto, Toshiaki; Yamamoto, Ikuo; Watanabe, Kazuhito

doi:10.1002/jps.22354

Cited by 23 publications

(29 citation statements)

References 44 publications

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“…⌬ 9 -THC inhibits (IC 50 ϭ 2.42 M) 15-lipoxygenase, an enzyme responsible for the formation of oxidized low-density lipoprotein, a causal factor for atherosclerosis (840).…”

Section: Cardiovascular Disordersmentioning

confidence: 99%

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

Ligresti¹,

Petrocellis²,

Marzo³

2016

Physiological Reviews

380

337

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Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS). This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one ⌬ 9 -tetrahydrocannabinol, and 2) the adaptive prohomeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs. In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field.

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“…⌬ 9 -THC inhibits (IC 50 ϭ 2.42 M) 15-lipoxygenase, an enzyme responsible for the formation of oxidized low-density lipoprotein, a causal factor for atherosclerosis (840).…”

Section: Cardiovascular Disordersmentioning

confidence: 99%

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

Ligresti¹,

Petrocellis²,

Marzo³

2016

Physiological Reviews

380

337

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“…CBDD (purity: > 98%) was prepared as described previously (Gohda et al, 1990;Takeda et al, 2009Takeda et al, , 2011aTakeda et al, , 2011b or obtained from Cayman Chemical Company (Ann Arbor, MI, USA).…”

Section: Methodsmentioning

confidence: 99%

“…The biological activities of cannabidiol (CBD), a major non-psychotropic constituent of the fiber-type cannabis plant, are well-known and include anti-cancer cell growth, migration, and invasion and anorectic effects (body weight loss) (Izzo et al, 2009;Takeda, 2013); however, those of CBD-2',6'-dimethyl ether (CBDD), a dimethyl ether derivative of the parent CBD (Gohda et al, 1990;Takeda et al, 2009Takeda et al, , 2011aTakeda et al, , 2011b (Fig. 1), have not yet been investigated in detail.…”

Section: Introductionmentioning

confidence: 99%

Cannabidiol-2’,6’-dimethyl ether stimulates body weight gain in apolipoprotein E-deficient BALB/c. KOR/Stm Slc-Apoeshl mice

et al. 2015

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-The biological activities of cannabidiol (CBD), a major non-psychotropic constituent of the fiber-type cannabis plant, have been examined in detail (e.g., CBD modulation of body weight in mice and rats). However, few studies have investigated the biological activities of cannabidiol-2',6'-dimethyl ether (CBDD), a dimethyl ether derivative of the parent CBD. We herein focused on the effects of CBDD on body weight changes in mice, and demonstrated that it stimulated body weight gain in apolipoprotein E (ApoE)-deficient BALB/c. KOR/Stm Slc-Apoe shl mice, especially between 10 and 20 weeks of age.

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“…[1][2][3][4][5][6][7][8][9][10][11] Given that Δ 9 -THC utilizes both these receptors in the induction of ERβ, specific respective antagonists would be effective in inhibiting ERβ induction stimulated by the cannabinoid. Because antagonists against CB1 and CB2 receptors (SR14716A and SR144528, respectively) were not effective in the abrogation of Δ 9 -THC induction of ERβ in human breast cancer MDA-MB-231 cells that express the two CB receptors (Takeda et al, unpublished observations), and because Δ 9 -THC also induced ERβ in human breast cancer MCF-7 cells that express very low or undetectable levels of CB receptors, 4,42) taken together, it is suggested that the two types of receptors are not essentially involved in the cannabinoid-mediated ERβ induction pathway(s) in breast cancer cells.…”

Section: Observations)mentioning

confidence: 99%

“…Δ 9 -THC exhibits a variety of pharmacological and toxicological effects: e.g., analgesia, hypotension, reduction of inflammation, and anticancer effects (anti-proliferative and anti-migration effects). [1][2][3][4][5][6][7][8][9][10][11] Among Δ 9 -THC's biological activities, its recognized endocrine-disrupting effects, including anti-estrogenic activity, have been the subjects of previous investigations. It has been reported that chronic oral administration of marijuana resin is able to reduce fertility in female rats.…”

Section: Introductionmentioning

confidence: 99%

Δ9-Tetrahydrocannabinol Targeting Estrogen Receptor Signaling: The Possible Mechanism of Action Coupled with Endocrine Disruption

Takeda

2014

Biological & Pharmaceutical Bulletin

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Δ9 -Tetrahydrocannabinol (Δ 9 -THC), a biologically active constituent of marijuana, possesses a wide variety of pharmacological and toxicological effects (e.g., analgesia, hypotension, reduction of inflammation, and anti-cancer effects). Among Δ 9 -THC's biological activities, its recognized anti-estrogenic activity has been the subject of investigations. Since Δ 9 -THC is used as both a drug of abuse (marijuana) and as a preventive therapeutic to treat pain and nausea in cancer patients undergoing chemotherapy in the United States and other countries (synthesized Δ 9 -THC; dronabinol), it is important to investigate the mechanistic basis underlying the anti-estrogenic activity of Δ 9 -THC. Since Δ 9 -THC has "no" binding potential for estrogen receptor α (ERα) which can be activated by estrogen (E2), the question of how Δ 9 -THC exerts its inhibitory effect on ERα is not resolved. We have recently reported that ERβ, a second type of ER, is involved in the Δ 9 -THC abrogation of E2/ERα-mediated transcriptional activity. Here we discuss the possible mechanism(s) of the Δ 9 -THC-mediated disruption of E2/ERα signaling by presenting our recent findings as well.

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Δ9-Tetrahydrocannabinol and Its Major Metabolite Δ9-Tetrahydrocannabinol-11-oic Acid as 15-Lipoxygenase Inhibitors

Cited by 23 publications

References 44 publications

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

Cannabidiol-2’,6’-dimethyl ether stimulates body weight gain in apolipoprotein E-deficient BALB/c. KOR/Stm Slc-<i>Apoe</i><i><sup>shl</sup></i> mice

Δ<sup>9</sup>-Tetrahydrocannabinol Targeting Estrogen Receptor Signaling: The Possible Mechanism of Action Coupled with Endocrine Disruption

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