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Antimicrobial Agents and Chemotherapy, August 2008, p. 2882-2889, Vol. 52, No. 8
0066-4804/08/$08.00+0     doi:10.1128/AAC.01505-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Zidovudine Impairs Adipogenic Differentiation through Inhibition of Clonal Expansion{triangledown}

Metodi V. Stankov, Reinhold E. Schmidt, Georg M. N. Behrens,* for the German Competence Network HIV/AIDS

Clinic for Clinical Immunology and Rheumatology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany

Received 20 November 2007/ Returned for modification 4 February 2008/ Accepted 2 May 2008

Lipoatrophy is a prevalent side effect of treatment with thymidine analogues. We wished to confine the time point of the antiadipogenic effect of zidovudine (AZT) during adipogenesis and to evaluate the antiproliferative effect of AZT on adipocyte homeostasis. We investigated the effects of AZT on adipogenesis in 3T3-F442A cells and studied their proliferation, differentiation, viability, and adiponectin expression. Cells were exposed to AZT (1 µM, 3 µM, 6 µM, and 180 µM), stavudine (d4T; 3 µM), or dideoxycytosine (ddC; 0.1 µM) for up to 15 days. Differentiation was assessed by real-time PCR and quantification of triglyceride accumulation. Proliferation and clonal expansion were determined by a [3H]thymidine incorporation assay. When they were induced to differentiate in the presence of AZT at the maximum concentration in plasma (Cmax) and lower concentrations, 3T3-F442A preadipocytes failed to accumulate cytoplasmic triacylglycerol and failed to express normal levels of the later adipogenic transcription factors, CCAAT/enhancer-binding protein {alpha} and peroxisome proliferator-activated receptor {gamma}. AZT exerted an inhibitory effect on the completion of the mitotic clonal expansion, which resulted in incomplete 3T3-F442A differentiation and, finally, a reduction in the level of adiponectin expression. In addition, AZT impaired the constitutive proliferation in murine and primary human subcutaneous preadipocytes. In contrast, incubation with d4T and ddC at the Cmax did not affect either preadipocyte proliferation or clonal expansion and differentiation. We conclude that the antiproliferative and antiadipogenetic effects of AZT on murine and primary human preadipocytes reveal the impact of the drug on fat tissue regeneration. These effects of the drug are expected to contribute to disturbed adipose tissue homeostasis and to be influenced by differential drug concentration and penetration in individual patients.

* Corresponding author. Mailing address: Clinic for Clinical Immunology and Rheumatology, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover 30625, Germany. Phone: 49 (0) 511 532 5713. Fax: 49 (0) 511 532 5324. E-mail: behrens.georg{at}mh-hannover.de

{triangledown} Published ahead of print on 12 May 2008.

Antimicrobial Agents and Chemotherapy, August 2008, p. 2882-2889, Vol. 52, No. 8
0066-4804/08/$08.00+0     doi:10.1128/AAC.01505-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Lynx, M. D., LaClair, D. D., McKee, E. E. (2009). Effects of Zidovudine and Stavudine on Mitochondrial DNA of Differentiating 3T3-F442a Cells Are Not Associated with Imbalanced Deoxynucleotide Pools. Antimicrob. Agents Chemother. 53: 1252-1255 [Abstract] [Full Text]  


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