Pharmacogenomics as Molecular Autopsy for Postmortem Forensic Toxicology: Genotyping Cytochrome P450 2D6 for Oxycodone Cases

Abstract

Pharmacogenomics, the study of the impact of heritable traits on pharmacology and toxicology, may serve as an adjunct for certifying opioid fatalities. Oxycodone, frequently prescribed for the relief of moderate to severe pain, is metabolized by cytochrome P450 (CYP) 2D6, encoded by a polymorphic gene with three mutations (*3, *4, and *5) with a combined 95% allelic frequency and about 10% prevalence. Individuals with variant alleles are more susceptible to oxycodone toxicity. By assessing the prevalence of CYP2D6 polymorphisms and covariables, we hypothesized that oxycodone fatality may be partially due to poor drug metabolism caused by CYP2D6 variant alleles. From the Milwaukee County Medical Examiner's Office (MCMEO), a retrospective analysis of 15 oxycodone cases was followed by genotyping blood samples for the variant alleles by conventional and real-time PCRs. Institutional Review Board approval was obtained. Oxycodone, extracted from blood and/or urine, was quantitated by GC-MS. The results show two homozygous for 2D6*4 and four heterozygous for 2D6*4. The MCMEO was not significantly different from those in the control group (n = 26) (p > 0.05, Fisher's Exact Test). However, genotyping CYP2D6 provided a more definitive interpretation of the oxycodone toxicity in four cases. Therefore, pharmacogenomics may serve as an adjunct in the determination of the cause and manner of death in forensic toxicology and a pharmacogenomic algorithm for genotyping has been proposed.

Sudden adult death

“…Nonetheless, a significant number of anatomically apparent causes of sudden death also have a heritable component; these and other subtle potential causes of sudden death should be excluded before resorting to a diagnosis of likely channelopathy. However, it is becoming apparent that genetic heterogeneity may account for individual susceptibilities [542][543][544]; thus it may be that genetics, including channelopathies, will be shown to play a role in explaining why sudden death occurs in some victims of chronic disease and not in others.…”

Molecular pathology in forensic medicine—Introduction

“…-determination of cause and manner of death [1][2][3][4]12,14,15,[18][19][20][21]31,38,39,56,57,60,[67][68][69]; -determination of the time since death or the age of bloodstains [8,9]; -tissue identification [5][6][7]10,73,74]; -wound age estimation; -toxicogenetics [25,26,34,35,41,42,49,55,62,66,71].…”

Pharmacogenetics and forensic toxicology

“…Genotyping provided a more definitive interpretation of oxycodone toxicity in four cases. Therefore, pharmacogenomics was proposed to serve as an adjunct in the determination of the cause and manner of death in forensic toxicology and a pharmacogenomic algorithm for genotyping has been proposed [84]. However, as also described by others [85], the PM genotype was rare and drug-drug interactions in EMs constituted a more frequent and important finding.…”