Pharmacogenomics as Molecular Autopsy for Forensic Toxicology: Genotyping Cytochrome P450 3A4*1B and 3A5*3 for 25 Fentanyl Cases
| Autor: | Ming Jin, Susan B. Gock, Jeffrey M. Jentzen, Steven H. Wong, Paul J. Jannetto |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Adult
Male medicine.medical_specialty Health Toxicology and Mutagenesis Pharmacology Toxicology Analytical Chemistry Fentanyl Cytochrome P-450 Enzyme System Cause of Death Internal medicine Cytochrome P-450 CYP3A Humans Environmental Chemistry Medicine Genotyping Aged Aged 80 and over Polymorphism Genetic Chemical Health and Safety CYP3A4 business.industry Homozygote Medical examiner Forensic toxicology Chronic pain Middle Aged Opioid-Related Disorders medicine.disease DNA Fingerprinting Analgesics Opioid Substance Abuse Detection Phenotype Pharmacogenetics Pharmacogenomics Toxicity Female Autopsy business medicine.drug |
| Zdroj: | Journal of Analytical Toxicology. 29:590-598 |
| ISSN: | 1945-2403 0146-4760 |
| DOI: | 10.1093/jat/29.7.590 |
| Popis: | Pharmacogenomics, the study on genetic contributions to drug action may help in certifying fentanyl toxicity. Fentanyl is used clinically as an adjunct to surgical anesthesia and for chronic pain management. Its toxicity may be partially due to cytochrome P450 (CYP) 3A4*1B and 3A5*3 variant alleles, resulting in variable fentanyl metabolism. In this study, we examined 25 fentanyl-related deaths (22 Caucasians, 1 African-American, and 2 Native-Americans) from the Milwaukee County Medical Examiner's Office and referral cases. Fentanyl and norfentanyl in postmortem blood samples were analyzed by radioimmunoassay and liquid chromatography-mass spectrometry-mass spectrometry. The samples were then genotyped for CYP3A4*1B and 3A5*3 using Pyrosequencing. Genotyping showed: 1 CYP3A4*1B homozygous and CYP3A5*3 heterozygous, 1 compound CYP3A4*1B and CYP3A5*3 heterozygous, 22 CYP3A4*1B wild type and CYP3A5*3 homozygous, and 1 CYP3A5*3 and CYP3A4*1B wild type. CYP variant allelic frequencies of the 25 cases were 6% for CYP3A4*1B and 92% for CYP3A5*3, compared with normal Caucasian CYP3A4*1B, 3-8%, and CYP3A5*3, 85-95%. The mean fentanyl concentration and metabolic ratio of fentanyl to norfentanyl of the 2 cases with CYP3A4*1B and CYP3A5*3 variants were 12.8 and 1.4 microg/L, respectively, lower than those of 22 cases with wild type CYP3A4*1B and CYP3A5*3 homozygous variants, 16.7 and 7.3 microg/L, respectively. The postmortem/in vivo data provided the first scientific evidence that CYP3A5 is involved in the fentanyl metabolism, and homozygous CYP3A5 *3 causes impaired metabolism of fentanyl, and genotyping CYP3A4*1B and 3A5*3 variants may help to certify the fentanyl toxicity. |
| Databáze: | OpenAIRE |
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