title: Effects of Zidovudine Treatment on Heart mRNA Expression and Mitochondrial DNA Copy Number Associated with Alterations in Deoxynucleoside Triphosphate Composition in a Neonatal Rat Model.
abstract: The prevention of mother-to-child transmission (MTCT) of HIV is a crucial component in HIV therapy. Nucleoside reverse transcriptase inhibitors (NRTIs), primarily 3'-azido-3'-thymidine (AZT [zidovudine]), have been used to treat both mothers and neonates. While AZT is being replaced with less toxic drugs in treating mothers in MTCT prevention, it is still commonly used to treat neonates. Problems related to mitochondrial toxicity and potential mutagenesis associated with AZT treatment have been reported in treated cohorts. Yet little is known concerning the metabolism and potential toxicity of AZT on embryonic and neonatal tissues, especially considering that the enzymes of nucleoside metabolism change dramatically as many tissues convert from hyperplastic to hypertrophic growth during this period. AZT is known to inhibit thymidine phosphorylation and potentially alter deoxynucleoside triphosphate (dNTP) pools in adults. This study examines the effects of AZT on dNTP pools, mRNA expression of deoxynucleoside/deoxynucleotide metabolic enzymes, and mitochondrial DNA levels in a neonatal rat model. Results show that AZT treatment dramatically altered dNTP pools in the first 7 days of life after birth, which normalized to age-matched controls in the second and third weeks. Additionally, AZT treatment dramatically increased the mRNA levels of many enzymes involved in deoxynucleotide synthesis and mitochondrial biogenesis during the first week of life, which normalized to age-matched controls by the third week. These results were correlated with depletion of mitochondrial DNA noted in the second week. Taken together, results demonstrated that AZT treatment has a powerful effect on the deoxynucleotide synthesis pathways that may be associated with toxicity and mutagenesis.
authors.affiliation: Foundational Sciences, College of Medicine, Central Michigan University, Mount Pleasant, Michigan, USA.
authors.forename: Jacob W
authors.initials: JW
authors.lastname: Snowdin
authors.affiliation: Foundational Sciences, College of Medicine, Central Michigan University, Mount Pleasant, Michigan, USA.
authors.forename: Chia-Heng
authors.initials: CH
authors.lastname: Hsiung
authors.affiliation: Foundational Sciences, College of Medicine, Central Michigan University, Mount Pleasant, Michigan, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Kesterson
authors.affiliation: Foundational Sciences, College of Medicine, Central Michigan University, Mount Pleasant, Michigan, USA.
authors.forename: Vasudeva G
authors.initials: VG
authors.lastname: Kamath
authors.affiliation: Foundational Sciences, College of Medicine, Central Michigan University, Mount Pleasant, Michigan, USA mckee1ee@cmich.edu.
authors.forename: Edward E
authors.initials: EE
authors.lastname: McKee
mesh_terms: D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000818:Animals; D000831:Animals, Newborn; D019380:Anti-HIV Agents / Q000633:toxicity*; D003570:Cytidine Triphosphate / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D056915:DNA Copy Number Variations / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D005260:Female; D005786:Gene Expression Regulation; D006160:Guanosine Triphosphate / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006321:Heart / Q000187:drug effects*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors / Q000633:toxicity*; D014544:Uridine Triphosphate / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015215:Zidovudine / Q000633:toxicity*
chemical_list: D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D003570:Cytidine Triphosphate; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D014544:Uridine Triphosphate