Ng Hanna H, Stock Howard, Rausch Linda, Bunin Deborah, Wang Abraham, Brill Shirley, Gow Jason, Mirsalis Jon C
Biosciences Division, SRI International, Menlo Park, CA, USA
Biosciences Division, SRI International, Menlo Park, CA, USA.
Int J Toxicol. 2015 Jan-Feb;34(1):4-10. doi: 10.1177/1091581814565669. Epub 2015 Jan 7.
Tenofovir disoproxil fumarate (TDF) is a prodrug of tenofovir that exhibits activity against HIV and hepatitis B. The goals of this study were to evaluate the molecular mechanism of TDF-induced toxicity in mice after 13 weeks of daily oral administration (50-1000 mg/kg) by correlating transcriptional changes with plasma drug levels and traditional toxicology end points. Plasma levels and systemic exposure of tenofovir increased less than dose proportionally and were similar on days 1 and 91. No overt toxicity was observed following the completion of TDF administration. The kidneys of TDF-treated mice were histopathologically normal. This result is consistent with the genomic microarray results, which showed no significant differences in kidney transcriptional levels between TDF-treated animals and controls. In liver, after 4 and 13 weeks, cytomegaly was observed in mice treated with 1000 mg/kg of TDF, but mice recovered from this effect following cessation of administration. Analysis of liver transcripts on day 91 reported elevated levels of Cdkn1a in TDF-treated animals compared with controls, which may have contributed to the inhibition of liver cell cycle progression.
富马酸替诺福韦二吡呋酯（TDF）是替诺福韦的前体药物，对HIV和乙型肝炎具有活性。本研究的目的是通过将转录变化与血浆药物水平及传统毒理学终点相关联，评估每日口服给药（50 - 1000 mg/kg）13周后TDF在小鼠中诱导毒性的分子机制。替诺福韦的血浆水平和全身暴露量的增加与剂量不成正比，且在第1天和第91天相似。完成TDF给药后未观察到明显毒性。经TDF处理的小鼠肾脏在组织病理学上正常。这一结果与基因组微阵列结果一致，该结果显示经TDF处理的动物与对照动物的肾脏转录水平无显著差异。在肝脏中，4周和13周后，用1000 mg/kg TDF处理的小鼠出现细胞肿大，但停药后小鼠从这种效应中恢复。第91天对肝脏转录本的分析报告显示，与对照相比，经TDF处理的动物中Cdkn1a水平升高，这可能导致了肝细胞周期进程的抑制。
