Stankov Metodi V, Schmidt Reinhold E, Behrens Georg M N
Clinic for Clinical Immunology and Rheumatology, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover 30625, Germany.
Antimicrob Agents Chemother. 2008 Aug;52(8):2882-9. doi: 10.1128/AAC.01505-07. Epub 2008 May 12.
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 microM, 3 microM, 6 microM, and 180 microM), stavudine (d4T; 3 microM), or dideoxycytosine (ddC; 0.1 microM) 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 [(3)H]thymidine incorporation assay. When they were induced to differentiate in the presence of AZT at the maximum concentration in plasma (C(max)) 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 C(max) 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.
脂肪萎缩是使用胸苷类似物治疗的一种常见副作用。我们希望确定齐多夫定（AZT）在脂肪生成过程中的抗脂肪生成作用的时间点，并评估AZT对脂肪细胞稳态的抗增殖作用。我们研究了AZT对3T3-F442A细胞脂肪生成的影响，并研究了它们的增殖、分化、活力和脂联素表达。将细胞暴露于AZT（1 microM、3 microM、6 microM和180 microM）、司他夫定（d4T；3 microM）或双脱氧胞苷（ddC；0.1 microM）长达15天。通过实时PCR和甘油三酯积累定量评估分化。通过[³H]胸苷掺入试验确定增殖和克隆扩增。当3T3-F442A前脂肪细胞在血浆最大浓度（C(max)）和较低浓度的AZT存在下被诱导分化时，它们无法积累细胞质三酰甘油，也无法表达后期脂肪生成转录因子CCAAT/增强子结合蛋白α和过氧化物酶体增殖物激活受体γ的正常水平。AZT对有丝分裂克隆扩增的完成产生抑制作用，导致3T3-F442A分化不完全，最终脂联素表达水平降低。此外，AZT损害了小鼠和原代人皮下前脂肪细胞的组成性增殖。相比之下，在C(max)下与d4T和ddC孵育既不影响前脂肪细胞增殖，也不影响克隆扩增和分化。我们得出结论，AZT对小鼠和原代人前脂肪细胞的抗增殖和抗脂肪生成作用揭示了该药物对脂肪组织再生的影响。该药物的这些作用预计会导致脂肪组织稳态紊乱，并受到个体患者药物浓度差异和渗透的影响。
