Potential pharmacogenetic inference in post-mortem investigation

The potential strength of pharmacogenetics in medico-legal context has been reported, even if the application in the medico-legal casework and the courtroom transposition need more scientific studies. When the cause of death (CoD) and/or the manner of death (MoD) are unclear or the toxicological results are difficult to explain, the pharmacogenetic investigation can be performed and the results need to be evidence-based interpreted [1]. Inter-individual variability in drug response derives from genetic polymorphisms in drug metabolizing enzymes which affect their function and lead to altered drug responses to a very large extent. In this respect, polymorphisms of the cytochrome P450 (CYP) enzymes play a major role being responsible for the metabolism of 70-80% of all phase I metabolism of clinically used drugs and participating in the metabolism of several xenobiotics [2]. The genetic bases of the polymorphism are single nucleotide polymorphisms, insertions/deletions and gene copy number variations and CYP2C9, CYP2C19 and CYP2D6 are the most polymorphic enzymes which mediate about 40% of P450-mediated drug metabolism [3]. The most extensively studied is the highly polymorphic CYP2D6 gene with up to date 109 allele variants permits to distinguish individuals in ultra-rapid metabolizers (gUM) normal metabolizers (gNM), intermediate metabolizers (gIM), and poor metabolizers (gPM) [4]. The extreme phenotypes (gPM and gUM) are the most important as they could lead to fatal adverse drug reactions or metabolic toxicity. Here we describe cases of drug addiction and fatal drug intoxication in which pharmacogenetic testing was applied for the interpretation of past organ failure and post-mortem toxicology results.