The Evaluation of CYP2D6, CYP2C9, CYP2C19, and CYP2B6 Phenoconversion in Post-Mortem Casework: The Challenge of Forensic Toxicogenetics

In toxicogenetics, an integrative approach including the prediction of phenotype based on post-mortem genotyping of drug-metabolising enzymes might help explain the cause of death (CoD) and manner of death (MoD). The use of concomitant drugs, however, might lead to phenoconversion, a mismatch between the phenotype based on the genotype and the metabolic profile actually observed after phenoconversion. The aim of our study was to evaluate the phenoconversion of CYP2D6, CYP2C9, CYP2C19, and CYP2B6 drug-metabolising enzymes in a series of autopsy cases tested positive for drugs that are substrates, inducers, or inhibitors of these enzymes. Our results showed a high rate of phenoconversion for all enzymes and a statistically significant higher frequency of poor and intermediate metabolisers for CYP2D6, CYP2C9, and CYP2C19 after phenoconversion. No association was found between phenotypes and CoD or MoD, suggesting that, although phenoconversion might be useful for a forensic toxicogenetics approach, more research is needed to overcome the challenges arising from the post-mortem setting.

Automated summary

In toxicogenetics, an integrative approach to predict phenotype based on post-mortem genotyping of drug-metabolizing enzymes can explain the cause of death and manner of death. However, concomitant drug use may lead to phenoconversion, resulting in a mismatch between genotype and observed metabolic profile. This study evaluated the phenoconversion of CYP2D6, CYP2C9, CYP2C19, and CYP2B6 drug-metabolizing enzymes in autopsy cases. Results showed a high rate of phenoconversion for all enzymes, with increased frequency of poor and intermediate metabolizers after phenoconversion. No association was found between phenotypes and cause/manner of death, indicating the need for further research in the post-mortem setting.