The intracellular localization of Δ9-tetrahydrocannabinol in liver and its effects on drug metabolism in vitro

Dingell, James V.; Miller, Kenneth W.; Heath, Eugene C.; Klausner, Howard

doi:10.1016/0006-2952(73)90219-0

Cited by 35 publications

(12 citation statements)

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“…While Δ 9 -THC is thought to utilize the same CB1 signaling pathway as the endocannabinoids AEA and 2-AG, little is known regarding molecular details of the intracellular trafficking of this highly lipophilic molecule. Within the blood, Δ 9 -THC is highly bound to serum lipoproteins and albumin. , However, >90% of Δ 9 -THC undergoes rapid hepatic clearance and metabolism within the liver. − Within the liver, Δ 9 -THC is localized primarily in the endoplasmic reticulum (wherein Δ 9 -THC oxidative enzymes are localized) and in the nucleus (wherein Δ 9 -THC regulates transcriptional activity of nuclear receptors in lipid and drug metabolism) . However, it is unclear if highly lipophilic membrane-associated molecules like Δ 9 -THC require cytosolic binding/chaperone proteins for trafficking through the cytoplasm and targeting to their sites of metabolism (endoplasmic reticulum) and transcriptional regulation (nucleus).…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Interaction of Δ⁹-Tetrahydrocannabinol with Liver Fatty Acid Binding Protein (FABP1)

et al. 2018

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Although serum Δ-tetrahydrocannabinol (Δ-THC) undergoes rapid hepatic clearance and metabolism, almost nothing is known regarding the mechanism(s) whereby this highly lipophilic phytocannabinoid is transported for metabolism/excretion. A novel NBD-arachidonoylethanolamide (NBD-AEA) fluorescence displacement assay showed that liver fatty acid binding protein (FABP1), the major hepatic endocannabinoid (EC) binding protein, binds the first major metabolite of Δ-THC (Δ-THC-OH) as well as Δ-THC itself. Circular dichroism (CD) confirmed that not only Δ-THC and Δ-THC-OH but also downstream metabolites Δ-THC-COOH and Δ-THC-CO-glucuronide directly interact with FABP1. Δ-THC and metabolite interaction differentially altered the FABP1 secondary structure, increasing total α-helix (all), decreasing total β-sheet (Δ-THC-COOH, Δ-THC-CO-glucuronide), increasing turns (Δ-THC-OH, Δ-THC-COOH, Δ-THC-CO-glucuronide), and decreasing unordered structure (Δ-THC, Δ-THC-OH). Cultured primary hepatocytes from wild-type (WT) mice took up and converted Δ-THC to the above metabolites. Fabp1 gene ablation (LKO) dramatically increased hepatocyte accumulation of Δ-THC and even more so its primary metabolites Δ-THC-OH and Δ-THC-COOH. Concomitantly, rtPCR and Western blotting indicated that LKO significantly increased Δ-THC's ability to regulate downstream nuclear receptor transcription of genes important in both EC ( Napepld > Daglb > Dagla, Naaa, Cnr1) and lipid ( Cpt1A > Fasn, FATP4) metabolism. Taken together, the data indicated that FABP1 may play important roles in Δ-THC uptake and elimination as well as Δ-THC induction of genes regulating hepatic EC levels and downstream targets in lipid metabolism.

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Section: Discussionmentioning

confidence: 99%

Structural and Functional Interaction of Δ⁹-Tetrahydrocannabinol with Liver Fatty Acid Binding Protein (FABP1)

et al. 2018

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“…The finding by Dinged ct al. [20] that THC primarily altered in vitro microsomal oxidation and reduction, but not conjugation, clearly implicates an in teraction with cytochrome P-450. Cohen et al [8] have shown that THC indeed com bines with hepatic microsomes to give a typ ical type I difference spectrum.…”

Section: Resultsmentioning

confidence: 99%

Effect of Long-Term Administration of Δ<sup>9</sup>-Tetrahydrocannabinol on Hepatic Mixed-Function Oxidase Systems in the Rat

Morrill¹,

O’Connell²,

Kostellow³

et al. 1985

Pharmacology

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Chronic oral treatment of young female Fischer rats with 25 mg/kg Δ⁹-tetrahydrocannabinol (THC) per day inhibited aminopyrine demethylation and significantly increased benzo[a]pyrene oxidation by the liver. THC treatment also elevated serum corticosterone levels and produced a significant loss of body weight. The weight loss was not due to vehicle or food intake (pair-feeding). Pair-feeding did, however, produce a stimulation of both mixed function oxidase pathways as well as a marked elevation in serum corticosterone levels. The results indicate that THC has a differential effect on mixed function oxidase pathways in the liver that is not directly related to food intake or corticosterone levels.

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“…The main psychoactive compound of herbal cannabis preparations, delta-9-tetrahydrocannabinol (D 9 -THC), displays an extraordinary affinity to biological membranes (Dingell et al, 1973;Seeman et al, 1972), causing its ability to interact directly with membrane lipids Koutselinis, 1979, 1980;Kalofoutis et al, 1978). This feature of D 9 -THC is crucial, as first-episode schizophrenia patients (Fukuzako, 2001;Keshavan et al, 2000;Stanley et al, 2000) and nonaffected twin siblings and offsprings of schizophrenia patients (Klemm et al, 2001) show alterations of cerebral phospholipid metabolites, suggesting abnormalities of lipid metabolism as part of a genetic vulnerability to develop psychosis.…”

Section: Introductionmentioning

confidence: 99%

Cannabinoids Influence Lipid–Arachidonic Acid Pathways in Schizophrenia

Smesny

Rosburg

Baur

et al. 2007

Neuropsychopharmacol

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Increasing evidence suggests modulating effects of cannabinoids on time of onset, severity, and outcome of schizophrenia. Efforts to discover the underlying pathomechanism have led to the assumption of gene Â environment interactions, including premorbid genetical vulnerability and worsening effects of continuing cannabis use. The objective of this cross-sectional study is to investigate the relationship between delta-9-tetrahydrocannabinol intake and niacin sensitivity in schizophrenia patients and healthy controls. Intensity of niacin skin flushing, indicating disturbed prostaglandin-mediated processes, was used as peripheral marker of lipid-arachidonic acid pathways and investigated in cannabis-consuming and nonconsuming schizophrenia patients and in healthy controls. Methylnicotinate was applied in three concentrations onto the forearm skin. Flush response was assessed in 3-min intervals over 15 min using optical reflection spectroscopy. In controls, skin flushing was significantly decreased in cannabis-consuming as compared to nonconsuming individuals. When comparing the nonconsuming subgroups, patients showed significantly decreased flush response. The populations as a whole (patients and controls) showed an inverse association between skin flushing and sum scores of Symptom Check List 90-R. Results demonstrate an impact of long-term cannabis use on lipid-arachidonic acid pathways. Considering pre-existing vulnerability of lipid metabolism in schizophrenia, observed effects of cannabis use support the notion of a gene Â environment interaction.

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The intracellular localization of Δ9-tetrahydrocannabinol in liver and its effects on drug metabolism in vitro

Cited by 35 publications

References 14 publications

Structural and Functional Interaction of Δ⁹-Tetrahydrocannabinol with Liver Fatty Acid Binding Protein (FABP1)

Structural and Functional Interaction of Δ⁹-Tetrahydrocannabinol with Liver Fatty Acid Binding Protein (FABP1)

Effect of Long-Term Administration of Δ<sup>9</sup>-Tetrahydrocannabinol on Hepatic Mixed-Function Oxidase Systems in the Rat

Cannabinoids Influence Lipid–Arachidonic Acid Pathways in Schizophrenia

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The intracellular localization of Δ9-tetrahydrocannabinol in liver and its effects on drug metabolism in vitro

Cited by 35 publications

References 14 publications

Structural and Functional Interaction of Δ9-Tetrahydrocannabinol with Liver Fatty Acid Binding Protein (FABP1)

Structural and Functional Interaction of Δ9-Tetrahydrocannabinol with Liver Fatty Acid Binding Protein (FABP1)

Effect of Long-Term Administration of &Delta;<sup>9</sup>-Tetrahydrocannabinol on Hepatic Mixed-Function Oxidase Systems in the Rat

Cannabinoids Influence Lipid–Arachidonic Acid Pathways in Schizophrenia

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Structural and Functional Interaction of Δ⁹-Tetrahydrocannabinol with Liver Fatty Acid Binding Protein (FABP1)

Structural and Functional Interaction of Δ⁹-Tetrahydrocannabinol with Liver Fatty Acid Binding Protein (FABP1)

Effect of Long-Term Administration of Δ<sup>9</sup>-Tetrahydrocannabinol on Hepatic Mixed-Function Oxidase Systems in the Rat