Characterization of Single Nucleotide Polymorphisms of Cytochrome P450 in an Australian Deceased Sample

Jennifer      L. Pilgrim; Yarimar      Ruiz; Alejandro      Gesteira; Raquel      Cruz; Dimitri      Gerostamoulos; Angel      Carracedo; Olaf      H. Drummer

Abstract

The genetically variable CYP450 isozymes are responsible for the metabolism of up to 80% of commonly used drugs, many of which are detected in cases of unexpected or suspicious death in Australia. The aim of this study was to examine the genetic profiles of individuals in a cohort of Australian deceased individuals dying of drug toxicity (219), natural disease (150), external injury (109) or unascertained (8) causes, to determine if there was an over-representation of individuals with a genetic predisposition to altered drug metabolism in cases attributed to drug toxicity compared with other causes. Single nucleotide polymorphisms (SNP) of CYP1A2, 2C9, 2C19, 2D6, 3A4 and 3A5 were analyzed. There were 27 cases (6.1%) that were CYP2D6 poor metabolizers (PM) and an additional 8 cases (1.7 %) that were CYP2C19 PMs. Around 31% of the cases were CYP2D6 intermediate-poor metabolizers, with a number of cases exhibiting drug combinations that were likely to have caused pharmacokinetic or pharmacodynamic interactions. There was no correlation between cause of death type and CYP2D6 metabolizer status. Increased enzyme activity was also indicated by the presence of hyperinducible variants such as CYP1A2*1F, which was observed at a frequency of 48%.

Keywords: CYP450, poor metabolizer, adverse drug reaction, fatalities, serotonergic drugs, Polymorphisms, Nucleotide, Cytochrome P450, isozymes, drug toxicity, CYP1A2, metabolizer, genotyping, subfamilies, Toxicological analysis