Mitochondrial toxicity in hearts of CD-1 mice following perinatal exposure to AZT, 3TC, or AZT/3TC in combination.

Mitochondrial toxicity in hearts of CD-1 mice following perinatal exposure to AZT, 3TC, or AZT/3TC in combination. Research Abstract Details 

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Mitochondrial toxicity in hearts of CD-1 mice following perinatal exposure to AZT, 3TC, or AZT/3TC in combination. Abstract Text:

Sherine S L Chan,Janine H Santos,Joel N Meyer,Bhaskar S Mandavilli,Dennis L Cook,Consuelo L McCash,Grace E Kissling,Abraham Nyska,Julie F Foley,Bennett van Houten,William C Copeland,Vernon E Walker,Kristine L Witt,Jack B Bishop,

Antiretroviral therapies based on nucleoside reverse transcriptase inhibitors (NRTIs), like zidovudine (3'-azido-3'-deoxythymidine; AZT) and lamivudine ((-)2',3'-dideoxy-3'-thiacytidine; 3TC), markedly reduce mother-to-child transmission of the human immunodeficiency virus (HIV). However, AZT induces damage in nuclear DNA of mice exposed in utero and postnatally, and mitochondrial DNA (mtDNA) damage has been observed in both human and mouse neonates following perinatal exposure to AZT and AZT/3TC in combination. To provide animal data modeling the NRTI-induced heart damage reported in human infants, we treated pregnant CD-1 mice throughout gestation and treated their pups by direct gavage from postnatal day (PND) 4 through PND 28 with daily doses of 150 mg/kg body weight (bw)/day AZT, 75 mg/kg bw/day 3TC, 125/62.5 mg/kg bw/day AZT/3TC, or the vehicle control. Half the pups were euthanized on PND 28; the remainder received no further dosing, and were euthanized at week 10. Heart tissue was collected, total DNA was extracted, and mtDNA copy number relative to nuclear DNA copy number, mtDNA damage, and mtDNA mutation assays were performed using PCR-based methods. Analyses revealed increases in mtDNA lesions in 4-week-old males and females treated with AZT or 3TC, but not in 10-week-old mice, suggesting that the damage resolved after treatment ceased. Interestingly, 10-week-old females treated with AZT/3TC had significant increases in mtDNA damage. Point mutations were elevated in 10-week-old females treated with AZT or AZT/3TC, but not 3TC; no increases in mutations were seen in either gender at 4 weeks of age. Our data suggest that AZT/3TC combination treatment produces greater mtDNA damage than either agent individually, and that female mice are more sensitive than males to AZT/3TC-induced mtDNA damage.

Mitochondrial toxicity in hearts of CD-1 mice following perinatal exposure to AZT, 3TC, or AZT/3TC in combination. Publishing Authors By Initials

SS Chan,JH Santos,JN Meyer,BS Mandavilli,DL Cook,CL McCash,GE Kissling,A Nyska,JF Foley,B van Houten,WC Copeland,VE Walker,KL Witt,JB Bishop,

For similar heterocyclic compounds: heterocyclic compounds, 1-ring: pyrimidines: pyrimidine nucleosides: thymidine: zidovudine research abstracts see: heterocyclic compounds: heterocyclic compounds, 1-ring: pyrimidines: pyrimidine nucleosides: thymidine: zidovudine research

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Mitochondrial toxicity in hearts of CD-1 mice following perinatal exposure to AZT, 3TC, or AZT/3TC in combination. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Environmental and molecular mutagenesis

VOLUME: 48

Page Numbers: 190-200

Journal Abbreviation: Environ. Mol. Mutagen.

ISSN: 0893-6692

DAY: 3

MONTH: 12

YEAR: 2007

Mitochondrial toxicity in hearts of CD-1 mice following perinatal exposure to AZT, 3TC, or AZT/3TC in combination. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 8800109

Mitochondrial toxicity in hearts of CD-1 mice following perinatal exposure to AZT, 3TC, or AZT/3TC in combination. Keywords Mesh Terms:

KEYWORDS: Zidovudine

MESH TERMS: toxicity

Chemical & Substance for Abstract: Mitochondrial toxicity in hearts of CD-1 mice following perinatal exposure to AZT, 3TC, or AZT/3TC in combination. Information

Substance Name: Prostaglandin-Endoperoxide Synthases

Registry Number: EC 1.14.99.1

Grant and Affiliation Information for Mitochondrial toxicity in hearts of CD-1 mice following perinatal exposure to AZT, 3TC, or AZT/3TC in combination.

AFFILIATION: Laboratory of Molecular Genetics, National Institute of Environmental HealthSciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.

Country: United States

AGENCY: United States NHLBI

GRANT: R01 HL072727

ACRONYM: HL

MEDLINETA: Environ Mol Mutagen

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