Heme metabolism after discontinued hexachlorobenzene administration in rats: possible irreversible changes and biomarker for hexachlorobenzene persistence

S.C Billi de Catabbi, C Aldonatti, L.C San Martin de Viale
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引用次数: 8

Abstract

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content and composition were studied in Wistar rats treated with the fungicide for 1, 2, 3, or 4 weeks and then withdrawn for a 20-week period.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.

停用六氯苯后大鼠血红素代谢:可能的不可逆变化和六氯苯持久性的生物标志物
本研究的目的是确定在没有外源性药物的情况下,短期给予六氯苯(HCB) (1 g/kg体重,悬浮在水中,每周5天)是否会导致并维持显著的卟啉症,以及卟啉参数是否可以作为大鼠HCB持久性的生物标志物。研究了Wistar大鼠用杀菌剂治疗1、2、3、4周后停药20周后肝脏尿卟啉原脱羧酶活性、抑制剂形成、卟啉含量和组成。研究尿卟啉排泄的时间过程为7周,或连续治疗整个周期,或1周HCB给药。大鼠在暂停给药20周后出现的卟啉程度非常严重,与治疗时间无关,甚至高于每次治疗结束时立即分析的动物。大鼠用HCB治疗1周后,尿卟啉原脱羧酶轻度下降,抑制剂形成低,在没有外源性药物的情况下,表现出更大的酶抑制、抑制剂形成、肝卟啉积累和卟啉组成模式的改变。独立于治疗,尿卟啉在延迟5周后上升。在20周的停药期后,在使用HCB治疗1周的大鼠脂肪中仍发现大量的HCB。这些结果表明,HCB在组织中的高持久性是一种持续的外源性来源,并刺激血红素生物合成紊乱。治疗1周内HCB诱导的改变可视为血红素代谢不可逆损伤的初始触发。因此,血红素生物合成异常可以被认为是HCB在大鼠体内持续存在或不可逆HCB引起的损伤的有效标志。考虑到HCB的延迟和增强代谢效应,建议不仅在暴露后立即评估卟啉参数,而且在一段时间后评估卟啉参数,特别是在易感和职业暴露人群中。
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