title: Is toxicity of PMMA (paramethoxymethamphetamine) associated with cytochrome P450 pharmacogenetics?
abstract: In 2010-2013, 29 fatal intoxications related to the designer drug paramethoxymethamphetamine (PMMA, 4-methoxymethamphetamine) occurred in Norway. The current knowledge about metabolism and toxicity of PMMA in humans is limited. Metabolism by the polymorphic cytochrome P450 (CYP) 2D6 enzyme to the psychoactive metabolite 4-hydroxymethamphetamine (OH-MA), and possibly by additional enzymes, is suggested to be involved in its toxicity. The aim of this work was to study the association between CYP genetics, PMMA metabolism and risk of fatal PMMA toxicity in humans. The frequency distribution of clinically relevant gene variants of CYP2D6, CYP2C9, CYP2C19 and CYP3A5, and the phenotypic blood CYP2D6 metabolic ratio (OH-MA/PMMA) in particular, were compared in fatal PMMA intoxications (n=17) and nonfatal PMMA abuse controls (n=30), using non-abusers (n=305) as references for the expected genotype frequencies in the Norwegian population. Our study demonstrated that the CYP2D6 enzyme and genotype are important in the metabolism of PMMA to OH-MA in humans, but that other enzymes are also involved in this biotransformation. In the fatal PMMA intoxications, the blood concentrations of PMMA were higher and the CYP2D6 metabolic ratios were lower, than in the nonfatal PMMA abuse controls (median (range) 2.1 (0.03-5.0) vs 0.3 (0.1-0.9) mg/L, and ratio 0.6 (0.0-4.6) vs 2.1 (0.2-7.4) p=0.021, respectively). Overall, our findings indicated that, in most cases, PMMA death occurred rapidly and at an early stage of PMMA metabolism, following the ingestion of large and toxic PMMA doses. We could not identify any genetic CYP2D6, CYP2C9, CYP2C19 or CYP3A5 predictive marker on fatal toxicity of PMMA in humans. The overrepresentation of the CYP2D6 poor metabolizer (PM) genotype found in the nonfatal PMMA abuse controls warrants further investigations.
authors.affiliation: Division of Forensic Sciences, Norwegian Institute of Public Health (NIPH), P.O. Box 4404, Nydalen, N-0403 Oslo, Norway. Electronic address: merete.vevelstad@fhi.no.
authors.forename: Merete
authors.initials: M
authors.lastname: Vevelstad
authors.affiliation: Division of Forensic Sciences, Norwegian Institute of Public Health (NIPH), P.O. Box 4404, Nydalen, N-0403 Oslo, Norway; School of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, 0316 Oslo, Norway. Electronic address: elisabeth.oiestad@fhi.no.
authors.forename: Elisabeth Leere
authors.initials: EL
authors.lastname: Øiestad
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital Rikshospitalet, P.O. Box 4950, N-0424 Oslo, Norway. Electronic address: sbremer@ous-hf.no.
authors.forename: Sara
authors.initials: S
authors.lastname: Bremer
authors.affiliation: Division of Forensic Sciences, Norwegian Institute of Public Health (NIPH), P.O. Box 4404, Nydalen, N-0403 Oslo, Norway. Electronic address: inger.lise.bogen@fhi.no.
authors.forename: Inger Lise
authors.initials: IL
authors.lastname: Bogen
authors.affiliation: National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Artillerigatan 12, SE-58758 Linkøping, Sweden. Electronic address: anna-lena.zackrisson@rmv.se.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Zackrisson
authors.affiliation: Division of Forensic Sciences, Norwegian Institute of Public Health (NIPH), P.O. Box 4404, Nydalen, N-0403 Oslo, Norway; Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway. Electronic address: marianne.arnestad@fhi.no.
authors.forename: Marianne
authors.initials: M
authors.lastname: Arnestad
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D015198:Designer Drugs / Q000032:analysis / Q000493:pharmacokinetics* / Q000506:poisoning; D005260:Female; D053593:Forensic Toxicology; D005838:Genotype; D006801:Humans; D008297:Male; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000506:poisoning; D008875:Middle Aged; D010597:Pharmacogenetics; D060888:Real-Time Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D015198:Designer Drugs; C106885:paramethoxymethamphetamine; D008694:Methamphetamine; D003577:Cytochrome P-450 Enzyme System
keywords: 4-Methoxymethamphetamine; CYP2D6 pharmacogenetics; Designer drugs; Forensic toxicology; PMMA; Paramethoxymethamphetamine