title: Mitochondrial ultrastructural and molecular changes induced by zidovudine in rat hearts.
abstract: Zidovudine (azidothymidine (AZT)) inhibits human immunodeficiency virus replication, prolongs survival, and delays progression of acquired immune deficiency syndrome. We determined AZT-induced molecular and ultrastructural changes in the rat heart. Rats (3 per group) were given drinking water with or without AZT (0.2 to 1.0 mg/ml; 29 to 102 mg/kg/day). After 21, 35, or 49 days, hearts were glutaraldehyde-fixed by abdominal aortic perfusion, processed, and examined by transmission electron microscopy. In parallel, myocardial RNA was extracted from hearts (AZT dose: 1 mg/ml; 35 days) and subjected to Northern analysis using cDNA probes for: alpha c-actin, troponin C, mitochondrial creatine kinase and malate dehydrogenase, a portion of the mitochondrial genome containing cytochrome b coding region (pMM26), and glyceraldehyde-3-phosphate dehydrogenase. Results showed marked and widespread cardiac mitochondrial swelling with fractured and disrupted cristae after 35 days of 1 mg/ml AZT. After a 14-day recovery, these ultrastructural defects did not reverse. Changes were not present in myocardium after 21 days of AZT nor after 35 days of lower dose AZT (0.2 mg/ml). Mitochondrial cytochrome b mRNA expression was depressed in AZT-treated rat hearts (35 days; 1 mg/ml AZT). mRNAs encoding glyceraldehyde-3-phosphate dehydrogenase, alpha c-actin, troponin C, mitochondrial creatine kinase, malate dehydrogenase, and mitochondrial ribosomal RNAs remained unchanged. AZT disrupts cardiac mitochondrial ultrastructure and expression of mitochondrial cytochrome b mRNA in a dose- and time-dependent fashion. The mechanism of AZT cardiotoxicity may relate to inhibition of mitochondrial DNA replication (at the level of DNA polymerase gamma) as postulated by others.
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA School of Medicine.
authors.forename: W
authors.initials: W
authors.lastname: Lewis
authors.forename: T
authors.initials: T
authors.lastname: Papoian
authors.forename: B
authors.initials: B
authors.lastname: Gonzalez
authors.forename: H
authors.initials: H
authors.lastname: Louie
authors.forename: D P
authors.initials: DP
authors.lastname: Kelly
authors.forename: R M
authors.initials: RM
authors.lastname: Payne
authors.forename: W W
authors.initials: WW
authors.lastname: Grody
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D004305:Dose-Response Relationship, Drug; D005260:Female; D006321:Heart / Q000187:drug effects*; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000473:pathology; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure*; D012313:RNA / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D015215:Zidovudine / Q000494:pharmacology*
chemical_list: D015215:Zidovudine; D012313:RNA