التفاصيل البيبلوغرافية
| العنوان: |
Pharmacology and Toxicology of Major Constituents of Marijuana—On the Metabolic Activation of Cannabinoids and Its Mechanism. |
| المؤلفون: |
Yamamoto, Ikuo, Watanabe, Kazuhito, Matsunaga, Tamihide, Kimura, Toshiyuki, Funahashi, Tatsuya, Yoshimura, Hidetoshi |
| المصدر: |
Journal of Toxicology -- Toxin Reviews; Nov2003, Vol. 22 Issue 4, p577-589, 13p, 6 Diagrams, 4 Charts, 1 Graph |
| مصطلحات موضوعية: |
MARIJUANA, CANNABINOIDS, PHARMACOLOGY, TOXICOLOGY, TETRAHYDROCANNABINOL, ALDEHYDES |
| مستخلص: |
Many oxidative metabolites of tetrahydrocannabinols (THCs), active components of Cannabis sativa L. (Cannabinaceae), were pharmacologically potent, and 11-hydroxy-THCs, 11-oxo-Δ8-THC, 7-oxo-Δ8-THC, 8β,9β-epoxyhexahydrocannabinol (EHHC), 9α,10α-EHHC and 3'-hydroxy-Δ9-THC were more active than THC in pharmacological effects such as catalepsy, hypothermia and barbiturate synergism in mice, indicating that these metabolites are active metabolites of THCs. Cannabidiol (CBD), another major component, was biotransfomred to two novel metabolites, 6-hydroxymethyl-Δ9-THC and 3-pentyl-6, 7, 7a, 8, 9, 11a-hexahydro-1, 7-dihydroxy-7,10-dimethyldibenzo[b,d]oxepin (PHDO) through 8R,9-epoxy-CBD and 8S, 9-epoxy-CBD as intermediates, respectively, identified by us. Both metabolites have some pharmacological effects comparable to Δ9-THC. Cannabinol (CBN), the other major component, was mainly metabolized to 11-hydroxy-CBN by hepatic microsomes of animals including humans. The pharmacological effects of the metabolite were higher than those of CBN demonstrating that 11-hydroxylation of CBN is an activation pathway of the cannabinoid as is the case in THCs. Tolerance developed to catalepsy, hypothermia and pentobarbital-induced sleep prolonging effects of Δ8-THC and its active metabolite, 11-hydroxy-Δ8-THC. Reciprocal cross-tolerance also developed to pharmacological effects and the magnitude of tolerance development produced by the metabolite was significantly higher than that by Δ8-THC indicating that 11-hydroxy-Δ8-THC has important role not only in the pharmacological effects but also its tolerance development of Δ8-THC. THCs and their metabolites competed with the specific binding of CP-55,940, an agonist of cannabinoid receptor, to synaptic membrane from bovine cerebral cortex. The Ki value of THCs and their metabolites were closely parallel to their pharmacological effects in mice. A novel cytochrome P450 (cyp2c29) was purified and identified for the first time by us as a major enzyme responsible for the metabolic activation of Δ8-THC at the 11-position in the mouse liver. cDNA of cyp2c29 was cloned from a mouse cDNA library and its sequence was determined. All of major P450s involving the metabolic activation of Δ8-THC at the 11-position are belonging to CYP2C subfamily in mammalian liver. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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