Dataset Information

Toxicogenetic analysis of ?9-THC-metabolizing enzymes.

ABSTRACT: While the impact of genetic polymorphisms on the metabolism of various pharmaceuticals is well known, more data are needed to better understand the specific influence of pharmacogenetics on the metabolism of delta 9-tetrahydocannabinol (?9-THC). Therefore, the aim of the study was to analyze the potential impact of variations in genes coding for phase I enzymes of the ?9-THC metabolism. First, a multiplex assay for genotyping different variants of genes coding for phase I enzymes was developed and applied to 66 ?9-THC-positive blood samples obtained in cases of driving under the influence of drugs (DUID). Genetic and demographic data as well as plasma concentrations of ?9-THC, 11-hydroxy-?9-tetrahydrocannabinol (11-OH-?9-THC), and 11-nor-9-carboxy-?9-THC (?9-THC-COOH) were combined and statistically investigated. For cytochrome P450 2C19 (CYP2C19) variants, no differences in analyzed cannabinoid concentrations were found. There were also no differences in the concentrations of ?9-THC and 11-OH-?9-THC for the different allelic CPY2C9 status. We recognized significantly lower ?9-THC-COOH concentrations for CYP2C9*3 (p?=?0.001) and a trend of lower ?9-THC-COOH concentrations for CYP2C9*2 which did not reach statistical significance (p?=?0.068). In addition, this study showed significantly higher values in the ratio of ?9-THC/?9-THC-COOH for the carriers of the CYP2C9 variants CYP2C9*2 and CYP2C9*3 compared with the carriers of the corresponding wild-type alleles. Therefore, an impact of variations of the CYP2C9 gene on the interpretation of cannabinoid plasma concentrations in DUID cases should be considered.

SUBMITTER: Gasse A

PROVIDER: S-EPMC7578149 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Toxicogenetic analysis of Δ9-THC-metabolizing enzymes.

Gasse Angela A Vennemann Marielle M Köhler Helga H Schürenkamp Jennifer J

International journal of legal medicine 20200725 6

While the impact of genetic polymorphisms on the metabolism of various pharmaceuticals is well known, more data are needed to better understand the specific influence of pharmacogenetics on the metabolism of delta 9-tetrahydocannabinol (Δ9-THC). Therefore, the aim of the study was to analyze the potential impact of variations in genes coding for phase I enzymes of the Δ9-THC metabolism. First, a multiplex assay for genotyping different variants of genes coding for phase I enzymes was developed a ...[more]

PMID: 32712703

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Project description:The prerequisites for responsible cannabis use are at the heart of current inquiries into cannabis decriminalization by policy makers as well as academic and nonacademic stakeholders at a global scale. Δ9-tetrahydrocannabinol (Δ9-THC), the prime psychoactive compound of the cannabis sativa, as well as cannabimimetics that resemble the pharmacological properties and psychological effects of Δ9-THC, lend themselves handsomely to the preclinical scrutiny of reward-related behavior because they carry marked translational value. Although a functional dichotomy of the psychological effects of Δ9-THC (rewarding versus aversive) has been abundantly reported in place conditioning (PC) paradigms, and might be best attributed to a dose-dependence of Δ9-THC, most PC studies with Δ9-THC feature no significant effects at all. Therefore, after decades of rigorous research, it still remains undetermined whether Δ9-THC generally exerts rewarding or aversive effects in rodents. Here, we set out to extrapolate the commonly alleged dose-dependence of the rewarding and aversive effects of Δ9-THC from the existing literature, at the behavioral pharmacological level of analysis. Specifically, our meta-analysis investigated: (i) the alleged bidirectional effects and dose-dependence of Δ9-THC in the PC test; (ii) methodological inconsistencies between PC studies; and (iii) other pharmacological studies on cannabinoids (i.e., dopamine release, anxiety, stress, conditioned taste aversion, catalepsy) to substantiate the validity of PC findings. Our findings suggest that: (i) Δ9-THC dose-dependently generates rewarding (1 mg/kg) and aversive (5 mg/kg) effects in PC; (ii) an inconsistent use of priming injections hampers a clear establishment of the rewarding effects of Δ9-THC in PC tests and might explain the seemingly contradictory plethora of nonsignificant THC studies in the PC test; and (iii) other pharmacological studies on Δ9-THC substantiate the dose-dependent biphasic effects of Δ9-THC in PC. A standardized experimental design would advance evidence-based practice in future PC studies with Δ9-THC and facilitate the pointed establishment of rewarding and aversive effects of the substance.

Dataset Information

Toxicogenetic analysis of ?9-THC-metabolizing enzymes.

Publications

Toxicogenetic analysis of Δ9-THC-metabolizing enzymes.

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