Single valproic acid treatment inhibits glycogen and RNA ribose turnover while disrupting glucose-derived cholesterol synthesis in liver as revealed by the [U-C(6)]-d-glucose tracer in mice.
Single valproic acid treatment inhibits glycogen and RNA ribose turnover while disrupting glucose-derived cholesterol synthesis in liver as revealed by the [U-C(6)]-d-glucose tracer in mice.
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DOI：
10.1007/s11306-009-0159-1
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发表时间：
2009-09
期刊：
影响因子：
3.6
通讯作者：
Boros, Laszlo G.
中科院分区：
文献类型：
--
作者：
Beger, Richard D.;Hansen, Deborah K.;Schnackenberg, Laura K.;Cross, Brandie M.;Fatollahi, Javad J.;Lagunero, F. Tracy;Sarnyai, Zoltan;Boros, Laszlo G.
先前的遗传和蛋白质组学研究发现，大鼠在单次中毒剂量丙戊酸（VPA）后，脂肪酸代谢和糖原合成等各种酶的活性发生了改变。在这项研究中，我们证明了VPA对代谢物合成通量率的影响，以及可能使用血浆或尿液中异常13C标记的葡萄糖衍生代谢物作为毒性的早期标志物。雌性CD-1小鼠皮下注射生理盐水或600 mg/kg VPA。12小时后，小鼠腹腔注射1 g/kg [U-13C]-d-葡萄糖。测定肝脏、肾脏和脑组织中糖原葡萄糖和RNA核糖的13C同位素，以及血浆和尿液中胆固醇和葡萄糖对葡萄糖的处理。血浆中葡萄糖的所有位置13C同位素水平相似，表明单剂量VPA不会干扰葡萄糖的吸收、摄取或肝脏葡萄糖代谢。三小时尿液样本显示，注射的示踪剂增加，表明葡萄糖通过肾小管的再吸收减少。经VPA处理后，13C标记的葡萄糖以肝糖原或核糖形式沉积；13C通过乙酰辅酶a掺入血浆胆固醇在60分钟显著降低。进入血浆的葡萄糖源碳通量和肾结合胆固醇、肝糖原和RNA核糖合成的严重减少，以及葡萄糖再吸收的减少和通过尿液处理的增加，都是vpa诱导的宿主不良代谢作用的早期通量标记。
Previous genetic and proteomic studies identified altered activity of various enzymes such as those of fatty acid metabolism and glycogen synthesis after a single toxic dose of valproic acid (VPA) in rats. In this study, we demonstrate the effect of VPA on metabolite synthesis flux rates and the possible use of abnormal 13C labeled glucose-derived metabolites in plasma or urine as early markers of toxicity. Female CD-1 mice were injected subcutaneously with saline or 600 mg/kg) VPA. Twelve hours later, the mice were injected with an intraperitoneal load of 1 g/kg [U-13C]-d-glucose. 13C isotopomers of glycogen glucose and RNA ribose in liver, kidney and brain tissue, as well as glucose disposal via cholesterol and glucose in the plasma and urine were determined. The levels of all of the positional 13C isotopomers of glucose were similar in plasma, suggesting that a single VPA dose does not disturb glucose absorption, uptake or hepatic glucose metabolism. Three-hour urine samples showed an increase in the injected tracer indicating a decreased glucose re-absorption via kidney tubules. 13C labeled glucose deposited as liver glycogen or as ribose of RNA were decreased by VPA treatment; incorporation of 13C via acetyl-CoA into plasma cholesterol was significantly lower at 60 min. The severe decreases in glucose-derived carbon flux into plasma and kidney-bound cholesterol, liver glycogen and RNA ribose synthesis, as well as decreased glucose re-absorption and an increased disposal via urine all serve as early flux markers of VPA-induced adverse metabolic effects in the host.
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影响因子：
5.5
作者：
COHEN, JJ;LITTLE, JR
通讯作者：
LITTLE, JR
影响因子：
3.9
作者：
Silva, MFB;Ijlst, L;Wanders, RJA
通讯作者：
Wanders, RJA
影响因子：
3.3
作者：
Schnackenberg, Laura K.;Jones, Richard C.;Dragan, Yvonne P.
通讯作者：
Dragan, Yvonne P.
DOI：
10.1007/bf03259935
发表时间：
1988-03-01
期刊：
MEDICAL TOXICOLOGY AND ADVERSE DRUG EXPERIENCE
影响因子：
--
作者：
EADIE, MJ;HOOPER, WD;DICKINSON, RG
通讯作者：
DICKINSON, RG
DOI：
10.1152/ajpendo.1999.277.6.e1022
发表时间：
1999-12-01
影响因子：
5.1
作者：
Puchowicz, MA;Bederman, IR;Brunengraber, H
通讯作者：
Brunengraber, H