title: Post-mortem ABCB1 genotyping reveals an elevated toxicity for female digoxin users.
abstract: BACKGROUND
  P-glycoprotein, a common transporter molecule, is known to affect metabolic functions in humans. Polymorphisms of the multidrug resistance gene (ABCB1/MDR1) coding for P-glycoprotein have been linked to changes in the processing of several commonly used medications in patients. Here, we have evaluated the impact of ABCB1 single nucleotide polymorphisms on digoxin fatality, through investigation of the relationship between post-mortem digoxin concentration and ABCB1 genotype.
  
  
  METHODS
  The effect of three ABCB1 single nucleotide polymorphisms (SNPs) (3435C>T, 1236C>T, and 2677G>T) on digoxin concentration was examined in 112 deceased Finnish subjects through RT-PCR genotyping of post-mortem blood samples. These subjects were selected on the basis of digoxin findings during the post-mortem toxicology screen, and categorized by digoxin concentration into three distinct groups. The distributions of mutant alleles and haplotypes in the deceased were compared to a random sample of 143 Finns.
  
  
  RESULTS
  Mutant genotype frequencies showed a positive relationship with post-mortem digoxin concentration for all SNPs. Female subjects showed a more emphatic pattern, suggesting a higher risk of digoxin intoxication.
  
  
  CONCLUSIONS
  These findings demonstrate a link between ABCB1 polymorphisms and increased mortality, and suggest that individualized genotyping should be considered prior to digoxin treatment. This research also exemplifies the value of gender-segregated genotyping studies in helping establish drug safety parameters, while allowing more decisive determination of cause and manner of death in a medico-legal context.
authors.affiliation: Department of Forensic Medicine, Hjelt-Institute, Laboratory of Forensic Biology, University of Helsinki, PO Box 40, (Kytösuontie 11), Helsinki, FI-00014, Finland. anu.neuvonen@helsinki.fi
authors.forename: Anu M
authors.initials: AM
authors.lastname: Neuvonen
authors.forename: Jukka U
authors.initials: JU
authors.lastname: Palo
authors.forename: Antti
authors.initials: A
authors.lastname: Sajantila
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D004077:Digoxin / Q000493:pharmacokinetics / Q000506:poisoning*; D005260:Female; D005387:Finland; D053803:Forensic Genetics; D005787:Gene Frequency; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D008297:Male; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004077:Digoxin