title: Tell-Tale SNPs: The Role of CYP2B6 in Methadone Fatalities.
abstract: Cytochrome P450 (CYP) enzyme 2B6 plays a significant role in the stereo-selective metabolism of (S)-methadone to 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine, an inactive methadone metabolite. Elevated (S)-methadone can cause cardiotoxicity by prolonging the QT interval of the heart's electrical cycle. Large inter-individual variability of methadone pharmacokinetics causes discordance in the relationship between dose, plasma concentrations and side effects. The purpose of this study was to determine if one or more single nucleotide polymorphisms (SNPs) located within the CYP2B6 gene contributes to a poor metabolizer phenotype for methadone in these fatal cases. The genetic analysis was conducted on 125 Caucasian methadone-only fatalities obtained from the West Virginia and Kentucky Offices of the Chief Medical Examiner. The frequency of eight exonic and intronic SNPs (rs2279344, rs3211371, rs3745274, rs4803419, rs8192709, rs8192719, rs12721655 and rs35979566) was determined. The frequencies of SNPs rs3745274 (*9, c516G > T, Q172H), and rs8192719 (21563 C > T) were enhanced in the methadone-only group. Higher blood methadone concentrations were observed in individuals who were genotyped homozygous for SNP rs3211371 (*5, c1459C > T, R487C). These results indicate that these three CYP2B6 SNPs are associated with methadone fatalities.
authors.affiliation: Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1700 Third Avenue, Huntington, WV 25755, USA.
authors.forename: Taha
authors.initials: T
authors.lastname: Ahmad
authors.affiliation: Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1700 Third Avenue, Huntington, WV 25755, USA.
authors.forename: Samie
authors.initials: S
authors.lastname: Sabet
authors.affiliation: Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1700 Third Avenue, Huntington, WV 25755, USA.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Primerano
authors.affiliation: Forensic Science Department, Marshall University, 1401 Forensic Science Drive, Huntington, WV 25701, USA.
authors.forename: Lauren L
authors.initials: LL
authors.lastname: Richards-Waugh
authors.affiliation: Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1700 Third Avenue, Huntington, WV 25755, USA.
authors.forename: Gary O
authors.initials: GO
authors.lastname: Rankin
mesh_terms: D000701:Analgesics, Opioid / Q000097:blood*; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics* / Q000378:metabolism; D062787:Drug Overdose / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D006801:Humans; D008691:Methadone / Q000097:blood*; D009293:Opioid-Related Disorders / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D020641:Polymorphism, Single Nucleotide
chemical_list: D000701:Analgesics, Opioid; D065702:Cytochrome P-450 CYP2B6; D008691:Methadone