Franklin M R, Phillips J D, Kushner J P
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 84112, USA.
Toxicol Appl Pharmacol. 1997 Dec;147(2):289-99. doi: 10.1006/taap.1997.8282.
An experimental model of porphyria cutanea tarda, consisting of depressed hepatic uroporphyrinogen decarboxylase (URO-D) activity and accumulation of highly carboxylated porphyrins in the liver, was produced in 3 weeks in Fischer 344 rats. A single administration of a polychlorinated biphenyl mixture (Aroclor 1254) to iron-loaded female rats maintained continuously on delta-aminolevulinic acid supplemented drinking water produced the porphyric state. Without iron loading, URO-D activity appeared slightly less inhibited (33% of normal vs 23% of normal) but porphyrin accumulation was dramatically less (70 vs 605 micrograms porphyrin/g liver). Similar treatment in male rats produced URO-D activities of 54 and 70% of normal with and without iron loading, respectively, and porphyrin concentrations of 76 and 17 micrograms/g. When hexachlorobenzene was substituted for Aroclor 1254 treatment in female rats, URO-D activity was 61 and 69% of normal (with and without iron loading, respectively) and liver porphyrin concentrations were 96 and 25 micrograms/g, respectively. Hexachlorobenzene did not produce significant porphyric effects in male rats. Aroclor 1254 induced CYP1A to a greater extent in females than in males and to a greater extent than hexachlorobenzene, which showed a greater propensity to induce CYP2B. Overall correlation between URO-D activity depression and porphyrin accumulation was highest when fitted to an exponential curve, indicating the importance of the extreme of the depression URO-D activity in evoking experimental porphyria cutanea tarda.
在3周内，通过降低肝尿卟啉原脱羧酶（URO-D）活性以及在肝脏中积累高度羧化的卟啉，在Fischer 344大鼠中建立了迟发性皮肤卟啉症的实验模型。给持续饮用补充了δ-氨基乙酰丙酸的饮水的铁负荷雌性大鼠单次给予多氯联苯混合物（Aroclor 1254），可产生卟啉症状态。在没有铁负荷的情况下，URO-D活性的抑制作用似乎略小（正常水平的33%对正常水平的23%），但卟啉积累显著减少（70微克卟啉/克肝脏对605微克卟啉/克肝脏）。对雄性大鼠进行类似处理时，无论有无铁负荷，URO-D活性分别为正常水平的54%和70%，卟啉浓度分别为76微克/克和17微克/克。当用六氯苯替代Aroclor 1254处理雌性大鼠时，URO-D活性分别为正常水平的61%和69%（分别有和没有铁负荷），肝脏卟啉浓度分别为96微克/克和25微克/克。六氯苯在雄性大鼠中未产生明显的卟啉症效应。Aroclor 1254对雌性大鼠CYP1A的诱导程度大于雄性大鼠，且大于六氯苯，六氯苯诱导CYP2B的倾向更大。当拟合指数曲线时，URO-D活性降低与卟啉积累之间的总体相关性最高，这表明URO-D活性降低的极端情况在引发实验性迟发性皮肤卟啉症中的重要性。
