Toxicogenetic analysis of Δ9-THC-metabolizing enzymes

Gasse, Angela; Vennemann, Marielle; Köhler, Helga; Schürenkamp, Jennifer

doi:10.1007/s00414-020-02380-3

Cited by 11 publications

(12 citation statements)

References 34 publications

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“…The threestep oxidative conversions of Δ 9 -THC, and also for CBD, into α,β-unsaturated carboxylic acid species are mediated by cytochrome P450 enzymes, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in particular. [215][216][217][218][219][220] Though experimental evidence is lacking, it is possible that the allylic alcohol moiety present in THC-and CBD-type phytocannabinoid metabolites can readily undergo further oxidative metabolism, while the corresponding saturated alcohol metabolites are less vulnerable to such CYP450-catalyzed oxidations. Since 11-OH-HHC appears to be nearly equipotent to Δ 9 -THC, 95,199 its accumulation in the body would result in prolonged (psycho)pharmacological effects relative to Δ 9 -THC.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Hexahydrocannabinol and closely related semi‐synthetic cannabinoids: A comprehensive review

Ujváry¹

2023

Drug Testing and Analysis

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Since the early 2000s, there has been a turmoil on the global illicit cannabinoid market. Parallel to legislative changes in some jurisdictions regarding herbal cannabis, unregulated and cheap synthetic cannabinoids with astonishing structural diversity have emerged. Recently, semi‐synthetic cannabinoids manufactured from hemp extracts by simple chemical transformations have also appeared as recreational drugs. The burst of these semi‐synthetic cannabinoids into the market was sparked by legislative changes in the United States, where cultivation of industrial hemp restarted. By now, hemp‐derived cannabidiol (CBD), initially a blockbuster product on its own, became a “precursor” to semi‐synthetic cannabinoids such as hexahydrocannabinol (HHC), which appeared on the drug market in 2021. The synthesis and cannabimimetic activity of HHC were first reported eight decades ago in quest for the psychoactive principles of marijuana and hashish. Current large‐scale manufacture of HHC is based on hemp‐derived CBD extract, which is converted first by cyclization into a Δ8/Δ9‐THC mixture, followed by catalytic hydrogenation to afford a mixture of (9R)‐HHC and (9S)‐HHC epimers. Preclinical studies indicate that (9R)‐HHC has THC‐like pharmacological properties. The animal metabolism of HHC is partially clarified. The human pharmacology including metabolism of HHC is yet to be investigated, and (immuno)analytical methods for the rapid detection of HHC or its metabolites in urine are lacking. Herein, the legal background for the revitalization of hemp cultivation, and available information on the chemistry, analysis, and pharmacology of HHC and related analogs, including HHC acetate (HHC‐O) is reviewed.

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Section: Pharmacokineticsmentioning

confidence: 99%

Hexahydrocannabinol and closely related semi‐synthetic cannabinoids: A comprehensive review

Ujváry¹

2023

Drug Testing and Analysis

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“…Individuals with *3 genotypes may have up to 300% higher THC levels and a 3-fold increased area under the curve (AUC) of THC and 70% lower concentration of inactive metabolite 11-COOH-THC in CYP2C9*3/*3 homozygotes compared with wild CYP2C9*1/*1 homozygotes [ 182 ]. A recent study confirmed significantly lower 11-COOH-THC concentrations for CYP2C9*3 and a trend to lower 11-COOH-THC concentrations for CYP2C9*2 carriers as well as significantly higher values of the ratio THC/11-COOH-THC for both carriers [ 189 ]. The data suggest that CYP2C9 polymorphisms may affect the formation of both active (11-OH-THC) and inactive (11-COOH-THC) metabolites.…”

Section: Pharmacogenomics Of Metabolismmentioning

confidence: 76%

“…However, 7-OH-CBD formation was not associated with the CYP2C19 genotype [ 43 ]. The polymorphism of the CYP2C19 gene did not impact the THC plasma concentrations [ 189 ]. This can be explained by the small proportion of the CYP2C19 enzyme in the metabolism of THC.…”

Section: Pharmacogenomics Of Metabolismmentioning

confidence: 99%

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Cannabis Pharmacogenomics: A Path to Personalized Medicine

Babayeva

Loewy

2023

CIMB

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Cannabis and related compounds have created significant research interest as a promising therapy in many disorders. However, the individual therapeutic effects of cannabinoids and the incidence of side effects are still difficult to determine. Pharmacogenomics may provide the answers to many questions and concerns regarding the cannabis/cannabinoid treatment and help us to understand the variability in individual responses and associated risks. Pharmacogenomics research has made meaningful progress in identifying genetic variations that play a critical role in interpatient variability in response to cannabis. This review classifies the current knowledge of pharmacogenomics associated with medical marijuana and related compounds and can assist in improving the outcomes of cannabinoid therapy and to minimize the adverse effects of cannabis use. Specific examples of pharmacogenomics informing pharmacotherapy as a path to personalized medicine are discussed.

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“…CADM2 is a synaptic cell-adhesion molecule (SynCAM family) in the immunoglobulin (Ig) superfamily [ 141 ]. It has been connected with alcohol consumption, reproductive success, and several personality traits, including a risk-taking, optimistic, and carefree character [ 142 , 143 ]. Three CADM2 polymorphisms, rs2875907, rs1448602, and rs7651996, have been linked with lifetime cannabis usage, according to a GWAS analysis of 184,765 individuals [ 143 ].…”

Section: Individuality Of Responsementioning

confidence: 99%

An Individuality of Response to Cannabinoids: Challenges in Safety and Efficacy of Cannabis Products

Kitdumrongthum

Trachootham

2023

Molecules

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Since legalization, cannabis/marijuana has been gaining considerable attention as a functional ingredient in food. ∆-9 tetrahydrocannabinol (THC), cannabidiol (CBD), and other cannabinoids are key bioactive compounds with health benefits. The oral consumption of cannabis transports much less hazardous chemicals than smoking. Nevertheless, the response to cannabis is biphasically dose-dependent (hormesis; a low-dose stimulation and a high-dose inhibition) with wide individuality in responses. Thus, the exact same dose and preparation of cannabis may be beneficial for some but toxic to others. The purpose of this review is to highlight the concept of individual variations in response to cannabinoids, which leads to the challenge of establishing standard safe doses of cannabis products for the general population. The mechanisms of actions, acute and chronic toxicities, and factors affecting responses to cannabis products are updated. Based on the literature review, we found that the response to cannabis products depends on exposure factors (delivery route, duration, frequency, and interactions with food and drugs), individual factors (age, sex), and susceptibility factors (genetic polymorphisms of cannabinoid receptor gene, N-acylethanolamine-hydrolyzing enzymes, THC-metabolizing enzymes, and epigenetic regulations). Owing to the individuality of responses, the safest way to use cannabis-containing food products is to start low, go slow, and stay low.

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Toxicogenetic analysis of Δ9-THC-metabolizing enzymes

Cited by 11 publications

References 34 publications

Hexahydrocannabinol and closely related semi‐synthetic cannabinoids: A comprehensive review

Hexahydrocannabinol and closely related semi‐synthetic cannabinoids: A comprehensive review

Cannabis Pharmacogenomics: A Path to Personalized Medicine

An Individuality of Response to Cannabinoids: Challenges in Safety and Efficacy of Cannabis Products

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