Toxicogenetic analysis of Δ9-THC-metabolizing enzymes

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 and applied to 66 Δ9-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 Δ9-THC, 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-Δ9-THC), and 11-nor-9-carboxy-Δ9-THC (Δ9-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 Δ9-THC and 11-OH-Δ9-THC for the different allelic CPY2C9 status. We recognized significantly lower Δ9-THC-COOH concentrations for CYP2C9*3 (p = 0.001) and a trend of lower Δ9-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 Δ9-THC/Δ9-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.