FABP1 controls hepatic transport and biotransformation of Δ9-THC
The increasing use of medical marijuana highlights the importance of developing a better understanding of cannabinoid metabolism. Phytocannabinoids, including ∆9-tetrahydrocannabinol (THC), are metabolized and inactivated by cytochrome P450 enzymes primarily within the liver. The lipophilic nature of cannabinoids necessitates mechanism(s) to facilitate their intracellular transport to metabolic enzymes. Here, we test the central hypothesis that liver-type fatty acid binding protein (FABP1) mediates phytocannabinoid transport and subsequent inactivation. Using X-ray crystallography, molecular modeling, and in vitro binding approaches we demonstrate that FABP1 accommodates one molecule of THC within its ligand binding pocket. Consistent with its role as a THC carrier, biotransformation of THC was reduced in primary hepatocytes obtained from FABP1-knockout (FABP1-KO) mice. Compared to their wild-type littermates, administration of THC to male and female FABP1-KO mice potentiated the physiological and behavioral effects of THC. The stark pharmacodynamic differences were confirmed upon pharmacokinetic analyses which revealed that FABP1-KO mice exhibit reduced rates of THC biotransformation. Collectively, these data position FABP1 as a hepatic THC transport protein and a critical mediator of cannabinoid inactivation. Since commonly used medications bind to FABP1 with comparable affinities to THC, our results further suggest that FABP1 could serve a previously unrecognized site of drug-drug interactions.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2019 |
|---|---|
| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
|---|---|
| Enthalten in: |
Scientific reports - 9(2019), 1 vom: 20. Mai, Seite 7588 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Elmes, Matthew W [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
7J8897W37S |
|---|
| Anmerkungen: |
Date Completed 16.10.2020 Date Revised 15.10.2021 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41598-019-44108-3 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM297287230 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM297287230 | ||
| 003 | DE-627 | ||
| 005 | 20231226200157.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2019 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41598-019-44108-3 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0990.xml |
| 035 | |a (DE-627)NLM297287230 | ||
| 035 | |a (NLM)31110286 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Elmes, Matthew W |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a FABP1 controls hepatic transport and biotransformation of Δ9-THC |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 16.10.2020 | ||
| 500 | |a Date Revised 15.10.2021 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a The increasing use of medical marijuana highlights the importance of developing a better understanding of cannabinoid metabolism. Phytocannabinoids, including ∆9-tetrahydrocannabinol (THC), are metabolized and inactivated by cytochrome P450 enzymes primarily within the liver. The lipophilic nature of cannabinoids necessitates mechanism(s) to facilitate their intracellular transport to metabolic enzymes. Here, we test the central hypothesis that liver-type fatty acid binding protein (FABP1) mediates phytocannabinoid transport and subsequent inactivation. Using X-ray crystallography, molecular modeling, and in vitro binding approaches we demonstrate that FABP1 accommodates one molecule of THC within its ligand binding pocket. Consistent with its role as a THC carrier, biotransformation of THC was reduced in primary hepatocytes obtained from FABP1-knockout (FABP1-KO) mice. Compared to their wild-type littermates, administration of THC to male and female FABP1-KO mice potentiated the physiological and behavioral effects of THC. The stark pharmacodynamic differences were confirmed upon pharmacokinetic analyses which revealed that FABP1-KO mice exhibit reduced rates of THC biotransformation. Collectively, these data position FABP1 as a hepatic THC transport protein and a critical mediator of cannabinoid inactivation. Since commonly used medications bind to FABP1 with comparable affinities to THC, our results further suggest that FABP1 could serve a previously unrecognized site of drug-drug interactions | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 7 | |a FABP1 protein, human |2 NLM | |
| 650 | 7 | |a Fabp1 protein, mouse |2 NLM | |
| 650 | 7 | |a Fatty Acid-Binding Proteins |2 NLM | |
| 650 | 7 | |a Dronabinol |2 NLM | |
| 650 | 7 | |a 7J8897W37S |2 NLM | |
| 700 | 1 | |a Prentis, Lauren E |e verfasserin |4 aut | |
| 700 | 1 | |a McGoldrick, Luke L |e verfasserin |4 aut | |
| 700 | 1 | |a Giuliano, Christopher J |e verfasserin |4 aut | |
| 700 | 1 | |a Sweeney, Joseph M |e verfasserin |4 aut | |
| 700 | 1 | |a Joseph, Olivia M |e verfasserin |4 aut | |
| 700 | 1 | |a Che, Joyce |e verfasserin |4 aut | |
| 700 | 1 | |a Carbonetti, Gregory S |e verfasserin |4 aut | |
| 700 | 1 | |a Studholme, Keith |e verfasserin |4 aut | |
| 700 | 1 | |a Deutsch, Dale G |e verfasserin |4 aut | |
| 700 | 1 | |a Rizzo, Robert C |e verfasserin |4 aut | |
| 700 | 1 | |a Glynn, Steven E |e verfasserin |4 aut | |
| 700 | 1 | |a Kaczocha, Martin |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Scientific reports |d 2011 |g 9(2019), 1 vom: 20. Mai, Seite 7588 |w (DE-627)NLM215703936 |x 2045-2322 |7 nnns |
| 773 | 1 | 8 | |g volume:9 |g year:2019 |g number:1 |g day:20 |g month:05 |g pages:7588 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41598-019-44108-3 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 9 |j 2019 |e 1 |b 20 |c 05 |h 7588 | ||