title: Morphine and Fentanyl Citrate Induce Retrotransposition of Long Interspersed Element-1.
abstract: The retroelement long interspersed element-1 (LINE-1 or L1) comprises about 17% of the human genome. A single human cell has 80 to 100 copies of retrotransposition-competent L1, approximately 10% of which are 'hot' and actively 'jump' around the genome. Recent observations demonstrated that low-molecular weight compounds may induce L1 retrotransposition through unknown mechanisms. Herein, we demonstrated that the painkillers morphine and fentanyl citrate trigger L1 retrotransposition in neuronal cells without inducing DNA damage or up-regulating L1 mRNA expression. This effect was blocked by an antagonist of Toll-like receptor 4 (TLR4). Taken together, the data suggest that L1 retrotransposition due to morphine and fentanyl citrate is distinct from that triggered by DNA damage, requires TLR4, and is a novel type of genomic instability. Thus, we propose that L1 retrotransposition should be characterized as a component of the pharmacological activity of these analgesic agents.
authors.affiliation: Division of Pharmacology, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry, Saitama, Japan Department of Legal Medicine, Hyogo College of Medicine, Hyogo, Japan noku@dent.meikai.ac.jp.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Okudaira
authors.affiliation: Department of Intractable Diseases, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Yukihito
authors.initials: Y
authors.lastname: Ishizaka
authors.affiliation: Department of Legal Medicine, Hyogo College of Medicine, Hyogo, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Nishio
authors.affiliation: Division of Pharmacology, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry, Saitama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakagami
mesh_terms: D002460:Cell Line; D005283:Fentanyl / Q000494:pharmacology*; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D023061:Gene Order; D005822:Genetic Vectors / Q000235:genetics; D042822:Genomic Instability; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D009020:Morphine / Q000494:pharmacology*; D016254:Mutagenesis, Insertional / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D018626:Retroelements; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D018626:Retroelements; D051197:Toll-Like Receptor 4; D009020:Morphine; D005283:Fentanyl
keywords: LINE-1; Morphine; TLR4; fentanyl citrate; retrotransposition