nach oben

Forensic Toxicology

Erschienen in:

01.07.2013 | Short Communication

Human brain microsomes: their abilities to metabolize tetrahydrocannabinols and cannabinol

verfasst von: Kazuhito Watanabe, Misa Miyamoto, Satoshi Yamaori, Koutaro Hasegawa, Kanako Watanabe, Osamu Suzuki

Erschienen in: Forensic Toxicology | Ausgabe 2/2013

Einloggen, um Zugang zu erhalten

Abstract

In spite of the psychedelic action of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) in the brain, no report on its metabolism by human brain microsomes has been published. In this study, the metabolism of Δ⁸-THC, Δ⁹-THC and cannabinol (CBN) was studied using human brain microsomes. The metabolites formed were analyzed by gas chromatography–mass spectrometry after trimethylsilylation. The three cannabinoids were biotransformed to two main metabolites by human brain microsomes. Δ⁸- and Δ⁹-THCs were mainly oxidized at the allylic positions. The main metabolites of Δ⁸-THC were 7α-hydroxy- and 11-hydroxy-Δ⁸-THCs, whereas those of Δ⁹-THC were 8α-hydroxy- and 11-hydroxy-Δ⁹-THCs. CBN was metabolized to 8-hydroxy- and 11-hydroxy-CBNs. Although the primary metabolic pathways of the THCs and CBN in brain microsomes are different from those in liver microsomes for other mammalian species, those in human brain microsomes were similar to those in human liver microsomes.

Uchiyama N, Kawamura M, Kikura-Hanajiri R, Goda Y (2012) Identification of two new-type synthetic cannabinoids, N-(1-adamantyl)-1-pentyl-1H-indole-3-carboxamide (APICA) and N-(1-adamantyl)-1-pentyl-1H-indole-3-carboxamide (APINACA), and detection of five synthetic cannabinoids, AM-1220, AM-2233, AM-1241, CB-13 (CRA-13), and AM-1248, as designer drugs in illegal products. Forensic Toxicol 30:114–125CrossRef

Papoutsis I, Nikolaou P, Dona A, Pistos C, Stefanidou M, Spiliopoulou C, Athanaselis S (2012) A validated GC-MS method for the determination of Δ⁹-tetrahydrocannabinol and 11-nor-Δ⁹-tetrahydrocannabinol-9-carboxylic acid in bile samples. Forensic Toxicol 30:51–58CrossRef

Tormey W, Moore T (2012) Inconsistent coroner interpretations of cardiac death in the presence of cannabis in urine. Forensic Toxicol 30:84–85CrossRef

Harvey DJ (1984) Chemistry, metabolism, and pharmacokinetics of the cannabinoids. In: Nahas GG (ed) Marijuana in science and medicine. Raven Press, New York, pp 37–107

Yamamoto I, Watanabe K, Narimatsu S, Yoshimura H (1995) Recent advances in the metabolism of cannabinoids. Int J Biochem Cell Biol 27:741–746PubMedCrossRef

Watanabe K, Yamaori S, Funahashi T, Kimura T, Yamamoto I (2007) Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sci 80:1415–1419PubMedCrossRef

Razdan RK (1986) Structure–activity relationships in cannabinoids. Pharm Rev 38:75–149PubMed

Yamamoto I, Watanabe K, Matsunaga T, Kimura T, Funahashi T, Yoshimura H (2003) Pharmacology and toxicology of marihuana—on the metabolic activation of cannabinoids and its mechanism. J Toxicol Toxin Rev 22:577–589CrossRef

Miksys SL, Tyndale RF (2002) Drug-metabolizing cytochrome P450 in the brain. J Psychiatry Neurosci 27:406–415PubMed

10.

Woodland C, Huang TT, Gryz E, Bendayan R, Fawcett JP (2008) Expression, activity and regulation of CYP3A in human and rodent brain. Drug Metab Rev 40:149–168PubMedCrossRef

11.

Watanabe K, Tanaka T, Yamamoto I, Yoshimura H (1988) Brain microsomal oxidation of Δ⁸- and Δ⁹-tetrahydrocannabinol. Biochem Biophys Res Commun 157:75–80PubMedCrossRef

12.

Watanabe K, Fujinami M, Yamaori S, Yamamoto I (2011) Possible involvement of Cyp3a enzymes in the metabolism of tetrahydrocannabinols by mouse brain microsomes. Forensic Toxicol 29:56–60CrossRef

13.

Aramaki H, Tomiyasu N, Yoshimura H, Tsukamoto H (1968) Forensic chemical study on marihuana. I. A detection method of the principal constituents by thin-layer and gas chromatographies. Chem Pharm Bull 16:822–826PubMedCrossRef

14.

Watanabe K, Yamaori S, Funahashi T, Kimura T, Yamamoto I (2006) 8-Hydroxycannabinol: a new metabolite of cannabinol formed by human hepatic microsomes. Forensic Toxicol 24:80–82CrossRef

15.

Watanabe K, Itokawa Y, Yamaori S, Funahashi T, Kimura T, Kaji T, Yamamoto I (2007) Conversion of cannabidiol to Δ⁹-tetrahydrocannabinol and related cannabinoids in artificial gastric juice, and their pharmacological effects in mice. Forensic Toxicol 25:16–21CrossRef

16.

Yamaori S, Maeda C, Yamamoto I, Watanabe K (2011) Differential inhibition of human cytochrome P450 2A6 and 2B6 by major phytocannabinoids. Forensic Toxicol 29:117–124CrossRef

17.

Mechoulam R, Varconi H, Ben-Zvi Z, Edery H, Grunfeld Y (1972) Synthesis and biological activity of five tetrahydrocannabinol metabolites. J Am Chem Soc 94:7930–7931PubMedCrossRef

18.

Inayama S, Sawa A, Hosoya E (1974) The oxidation of Δ¹- and Δ⁶-tetrahydrocannabinol with selenium dioxide. Chem Pharm Bull 22:1519–1525PubMedCrossRef

19.

Pitt CG, Fowler MS, Sathe S, Srivastava SC, Williams DL (1975) Synthesis of metabolites of Δ⁹-tetrahydrocannabinol. J Am Chem Soc 97:3798–3802PubMedCrossRef

20.

Yamamoto I, Narimatsu S, Watanabe K, Shimonishi T, Yoshimura H, Nagano T (1983) Human liver microsomal oxidation of Δ⁸-tetrahydrocannabinol. Chem Pharm Bull 31:1784–1787PubMedCrossRef

21.

Bornheim LM, Lasker JM, Raucy JL (1992) Human hepatic microsomal metabolism of Δ¹-tetrahydrocannabinol. Drug Metab Dispos 20:241–246PubMed

22.

Burstein SH, Kupfer D (1971) Hydroxylation of trans-Δ¹-tetrahydrocannabinol by a hepatic microsomal monooxygenase. Chem-Biol Interact 3:316PubMedCrossRef

23.

Ben-Zvi Z, Burstein S, Zikopoulos J (1974) Metabolism of Δ¹-tetrahydrocannabinol by mouse hepatic microsomes: identification of 6α-hydroxytetrahydrocannabinol. J Pharm Sci 63:1173–1174PubMedCrossRef

24.

Ben-Zvi Z, Burstein S (1975) Transformation of Δ¹-tetrahydrocannabinol (THC) by rabbit liver microsomes. Biochem Pharmacol 24:1130–1131PubMedCrossRef

25.

Watanabe K, Narimatsu S, Matsunaga T, Yamamoto I, Yoshimura H (1992) A cytochrome P450 isozyme having aldehyde oxygenase activity plays a major role in metabolizing cannabinoids by mouse hepatic microsomes. Biochem Pharmacol 46:405–411CrossRef

26.

Pai HV, Upadhya SC, Chinta SJ, Hegde SN, Ravindranath V (2002) Differential metabolism of alprazolam by liver and brain cytochrome (P4503A) to pharmacologically active metabolite. Pharmacogenomics J 2:243–258PubMedCrossRef

27.

Agarwal V, Kommaddi P, Valli K, Ryder D, Hyde TM, Kleinman JE, Strobel HW, Ravindranath V (2008) Drug metabolism in human brain: high levels of cytochrome P4503A43 in brain and metabolism of anti-anxiety drug alprazolam to its active metabolite. PLoS ONE 3(6):e2337. doi:10.1371/journal.pone.0002337 PubMedCrossRef

28.

Christensen HD, Freudenthal RI, Gidley GT, Rosenfeld R, Boegli G, Testino L, Brine DR, Pitt CG, Wall ME (1971) Activity of Δ⁸- and Δ⁹-tetrahydrocannabinol and related compounds in the mouse. Science 172:165–167PubMedCrossRef

29.

Watanabe K, Yamamoto I, Oguri K, Yoshimura H (1980) Comparison in mice of pharmacological effects of Δ⁸-tetrahydrocannabinol oxidized at 11-position. Eur J Pharmacol 63:1–6PubMedCrossRef

30.

Yamamoto I, Watanabe K, Kuzuoka K, Narimatsu S, Yoshimura H (1987) The pharmacological activity of cannabinol and its major metabolite, 11-hydroxycannabinol. Chem Pharm Bull 35:2144–2147PubMedCrossRef

Titel: Human brain microsomes: their abilities to metabolize tetrahydrocannabinols and cannabinol
verfasst von: Kazuhito Watanabe
Misa Miyamoto
Satoshi Yamaori
Koutaro Hasegawa
Kanako Watanabe
Osamu Suzuki
Publikationsdatum: 01.07.2013
Verlag: Springer Japan
Erschienen in: Forensic Toxicology / Ausgabe 2/2013
Print ISSN: 1860-8965
Elektronische ISSN: 1860-8973
DOI: https://doi.org/10.1007/s11419-013-0181-x

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Human brain microsomes: their abilities to metabolize tetrahydrocannabinols and cannabinol

Abstract

Neu im Fachgebiet Rechtsmedizin

Molekularpathologische Untersuchungen im Wandel der Zeit

Vergleichende Pathologie in der onkologischen Forschung

Gastrointestinale Stromatumoren

Personalisierte Medizin in der Onkologie

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 2/2013

Does duration of wearing a disposable diaper in newborns influence testing for methamphetamine from urine absorbed in the diaper when using conventional immunoassay devices?

[1-(Tetrahydropyran-4-ylmethyl)-1H-indol-3-yl]-(2,2,3,3-tetramethylcyclopropyl)methanone: a new synthetic cannabinoid identified on the drug market

A fatal case of 3,4-methylenedioxypyrovalerone poisoning: coexistence of α-pyrrolidinobutiophenone and α-pyrrolidinovalerophenone in blood and/or hair

SPME–GC–MS analysis of α-pyrrolidinovaleorophenone in blood in a fatal poisoning case

In vitro and in vivo metabolisms of 1-pentyl-3-(4-methyl-1-naphthoyl)indole (JWH-122)

Differentiation of regioisomeric fluoroamphetamine analogs by gas chromatography–mass spectrometry and liquid chromatography–tandem mass spectrometry

Neu im Fachgebiet Rechtsmedizin

Molekularpathologische Untersuchungen im Wandel der Zeit

Vergleichende Pathologie in der onkologischen Forschung

Gastrointestinale Stromatumoren

Personalisierte Medizin in der Onkologie