Gorman Nadia, Zaharia Adrian, Trask Heidi S, Szakacs Juliana G, Jacobs Nicholas J, Jacobs Judith M, Balestra Dominic, Sinclair Jacqueline F, Sinclair Peter R
VA Medical Center, White River Junction, VT 05009, USA.
Hepatology. 2007 Jan;45(1):187-94. doi: 10.1002/hep.21474.
Excess hepatic iron is known to enhance both porphyria cutanea tarda (PCT) and experimental uroporphyria. Since previous studies have suggested a role for ascorbate (AA) in suppressing uroporphyria in AA-requiring rats (in the absence of excess iron), the present study investigated whether AA could suppress uroporphyria produced by excess hepatic iron. Hepatic URO accumulation was produced in AA-requiring Gulo(-/-) mice by treatment with 3,3',4,4',5-pentachlorbiphenyl, an inducer of CYP1A2, and 5-aminolevulinic acid. Mice were administered either sufficient AA (1000 ppm) in the drinking water to maintain near normal hepatic AA levels or a lower intake (75 ppm) that resulted in 70 % lower hepatic AA levels. The higher AA intake suppressed hepatic URO accumulation in the absence of administered iron, but not when iron dextran (300-500 mg Fe/kg) was administered. This effect of iron was not due to hepatic AA depletion since hepatic AA content was not decreased. The effect of iron to prevent AA suppression of hepatic URO accumulation was not observed until a high hepatic iron threshold was exceeded. At both low and high AA intakes, hepatic malondialdehyde (MDA), an indicator of oxidative stress, was increased three-fold by high doses of iron dextran. MDA was considerably increased even at low iron dextran doses, but without any increase in URO accumulation. The level of hepatic CYP1A2 was unaffected by either AA intake.
In this mouse model of PCT, AA suppresses hepatic URO accumulation at low, but not high hepatic iron levels. These results may have implications for the management of PCT.
已知肝脏铁过载会加重迟发性皮肤卟啉病（PCT）和实验性尿卟啉病。由于先前的研究表明抗坏血酸（AA）在需要AA的大鼠中（在没有铁过载的情况下）对抑制尿卟啉病起作用，本研究调查了AA是否能抑制肝脏铁过载产生的尿卟啉病。通过用CYP1A2诱导剂3,3',4,4',5-五氯联苯和5-氨基乙酰丙酸处理需要AA的Gulo(-/-)小鼠，产生肝脏尿卟啉原（URO）蓄积。给小鼠饮用含足够AA（1000 ppm）的水以维持接近正常的肝脏AA水平，或摄入较低量（75 ppm）的AA，导致肝脏AA水平降低70%。在未给予铁的情况下，较高的AA摄入量可抑制肝脏URO蓄积，但给予右旋糖酐铁（300 - 500 mg Fe/kg）时则不能。铁的这种作用并非由于肝脏AA耗竭，因为肝脏AA含量并未降低。直到超过高肝脏铁阈值时，才观察到铁对AA抑制肝脏URO蓄积的预防作用。在低和高AA摄入量时，高剂量的右旋糖酐铁均使肝脏丙二醛（MDA，氧化应激指标）增加三倍。即使在低剂量的右旋糖酐铁时，MDA也显著增加，但URO蓄积没有任何增加。肝脏CYP1A2水平不受AA摄入量的影响。
在这个PCT小鼠模型中，AA在低肝脏铁水平时可抑制肝脏URO蓄积，但在高肝脏铁水平时则不能。这些结果可能对PCT的治疗有启示。
