AZT treatment induces molecular and ultrastructural oxidative damage to muscle mitochondria. Prevention by antioxidant vitamins.
Year: 1998
Type: article
Abstract: AIDS patients who receive zidovudine (AZT) frequently suffer from myopathy.This has been attributed to mitochondrial (mt) damage, and specifically to the loss of mtDNA.This study examines whether AZT causes oxidative damage to DNA in patients and to skeletal muscle mitochondria in mice, and whether this damage may be prevented by supranutritional doses of antioxidant vitamins.Asymptomatic HIV-infected patients treated with AZT have a higher urinary excretion (355 Ϯ 100 pmol/kg/d) of 8-oxo-7,8-dihydro-2 Ј -deoxyguanosine (8-oxo-dG) (a marker of oxidative damage to DNA) than untreated controls (asymptomatic HIV-infected patients) (182 Ϯ 29 pmol/kg/d).This was prevented (110 Ϯ 79 pmol/kg/d) by simultaneous oral treatment with AZT plus antioxidant vitamins (C and E).Mice treated with AZT also had a significantly higher urinary excretion of 8-oxo-dG than controls.Skeletal muscle mtDNA of mice treated with AZT had more 8-oxo-dG than controls.mt lipoperoxidation was also increased and skeletal muscle glutathione was oxidized.These effects may be due to an increased peroxide production by muscle mitochondria of AZT-treated animals.Dietary supplements with vitamins C and E at supranutritional doses protect against oxidative damage to skeletal muscle mitochondria caused by AZT. ( J. Clin.Invest.1998.102:4-9.)Key words: 8-dihydro-2 Ј -deoxyguanosine • AZT • mitochondrial DNA damage • oxidative damage • antioxidant vitamins Methods Chemicals.RNAase (E.C.3.1.27.5) from bovine pancreas was purchased from Boehringer-Mannheim (Mannheim, Germany).Water and methanol (HPLC grade) were from Merck (Darmstadt, Germany).Nuclease P1 (E.C.3.1.30.1) was from P. Citricum.Alkaline phosphatase type III-L (C.E.3.1.3.1) was isolated from Escherichia coli.Glutathione-S -transferase (E.C.2.5.1.18)was isolated from equine liver.GSH, oxidized glutathione (GSSG), 8-oxo-dG, AZT, (3 Ј -azido-3 Ј -deoxythymidine) N -ethylmalemide (NEM), bathophenanthroline disulfonic acid (BPDS), Mops, BSA, and all other reagents were purchased from Sigma Chemical Co.(St.Louis, MO).Patients.We analyzed urine from 23 30 Ϯ 3-yr-old male adults weighing 70 Ϯ 7 kg.Urine samples were collected from each individual 24 h void and stored at Ϫ 30 Њ C until analysis.Four groups were studied: ( A ) healthy controls, ( B ) HIV-positive patients (who had not received AZT) with 570 Ϯ 261 CD 4 ϩ / l, ( C ) HIV-positive patients treated with AZT (Retrovir ® , 250 mg/12 h) over 12-24 mo with 382 Ϯ 141 CD 4 ϩ / l, and ( D ) the same HIV-positive patients who were
DOI: 10.1172/jci1418
Institution: Universitat de València
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2002644253