Aldonatti C, de Viale L C
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina.
Comp Biochem Physiol C Toxicol Pharmacol. 2000 Sep;127(2):165-75. doi: 10.1016/s0742-8413(00)00149-3.
The aim of the present study was to determine whether short-term administration of hexachlorobenzene (HCB) (1 g/kg body wt., suspended in water, 5 days/week), could cause and maintain marked porphyria in the absence of the exogenous drug, and whether porphyria parameters can be useful as biomarkers of HCB persistence in rats. Hepatic uroporphyrinogen decarboxylase activity, its inhibitor formation, porphyrin content and composition were studied in Wistar rats treated with the fungicide for 1, 2, 3, or 4 weeks and then withdrawn for a 20-week period. The time course of urinary porphyrin excretion was studied for 7 weeks either by continuous treatment for the entire period, or a 1-week HCB administration. The degree of porphyria achieved by rats after 20 weeks of suspended HCB administration was severe, independent of the length of the treatment, and even higher than that observed in animals analysed immediately at the end of each treatment. Rats treated with HCB for 1 week showed a modest decrease in uroporphyrinogen decarboxylase and low inhibitor formation, and exhibited a greater enzyme inhibition, inhibitor formation, hepatic porphyrin accumulation, and an altered pattern of porphyrin composition in the absence of the exogenous drug. Independent of the treatment, urinary porphyrins rose after a delay of 5 weeks. Substantial amounts of HCB were still found in fat of rats treated with HCB for 1 week, after a withdrawal period of 20 weeks. These results suggest that the high persistence of HCB in tissues acts as a continuous source of the xenobiotic, and stimulus for heme biosynthesis derangement. The alterations induced by HCB within 1 week of treatment could be regarded as an initial trigger for irreversible damage on heme metabolism. Thus, abnormalities in heme biosynthesis can be considered effective markers of HCB persistence in rats or of irreversible HCB-induced damage. Taking into account the delayed and enhanced metabolic effects of HCB, it is advisable that porphyria parameters should be evaluated not only immediately after exposure, but also some time afterwards, especially in susceptible and occupationally-exposed populations.
本研究的目的是确定短期给予六氯苯（HCB）（1克/千克体重，悬浮于水中，每周5天）是否能在无外源性药物的情况下引发并维持明显的卟啉症，以及卟啉症参数是否可作为HCB在大鼠体内持久性的生物标志物。对用该杀菌剂处理1、2、3或4周，然后停药20周的Wistar大鼠，研究了肝脏尿卟啉原脱羧酶活性、其抑制剂形成、卟啉含量及组成。通过整个时期的持续处理或1周的HCB给药，研究了7周内尿卟啉排泄的时间进程。HCB停药20周后，大鼠达到的卟啉症程度严重，与治疗时长无关，甚至高于每次治疗结束时立即分析的动物中观察到的程度。用HCB处理1周的大鼠，尿卟啉原脱羧酶略有下降且抑制剂形成较少，在无外源性药物的情况下表现出更大的酶抑制、抑制剂形成、肝脏卟啉积累及卟啉组成模式改变。与治疗无关，尿卟啉在延迟5周后升高。在停药20周后，用HCB处理1周的大鼠脂肪中仍发现大量HCB。这些结果表明，HCB在组织中的高持久性作为外源性物质的持续来源，以及血红素生物合成紊乱的刺激因素。HCB在治疗1周内引起的改变可被视为对血红素代谢不可逆损伤的初始触发因素。因此，血红素生物合成异常可被视为HCB在大鼠体内持久性或HCB诱导的不可逆损伤的有效标志物。考虑到HCB的延迟和增强的代谢效应，建议不仅在接触后立即评估卟啉症参数，而且在之后的一段时间也进行评估，特别是在易感和职业暴露人群中。
