den Besten C, Bennik M H, Bruggeman I, Schielen P, Kuper F, Brouwer A, Koeman J H, Vos J G, Van Bladeren P J
Department of Toxicology, Agricultural University, Wageningen, The Netherlands.
Toxicol Appl Pharmacol. 1993 Apr;119(2):181-94. doi: 10.1006/taap.1993.1059.
Hexachlorobenzene (HCB) induces a broad spectrum of effects including disturbances in the heme synthesis (porphyria) and in thyroid hormone homeostasis. For most of its effects, biotransformation of the parent compound seems to be a prerequisite. The present study was designed to assess the relevance of the oxidative metabolites in HCB-induced toxicity, with special attention to the role of the reactive tetrachlorobenzoquinone (TCBQ). To this end, toxicity and biotransformation of HCB were compared with those of pentachlorobenzene (PCB), since this chemical is oxidized to the same products as HCB, i.e., pentachlorophenol (PCP) and TCBQ. Female Wistar rats received diets containing different dose levels of HCB or PCB for 13 weeks, with or without cotreatment with triacetyloleandomycin (TAO), a selective inhibitor of cytochrome P450IIIA1/2. Rats treated with HCB (high dose) had significantly elevated levels of urinary porphyrins from the 4th week on and had a significant hepatic accumulation of porphyrins at the end of the study. Both urinary porphyrin excretion and hepatic porphyrin accumulation were greatly inhibited in rats receiving cotreatment with HCB and TAO. However, the inhibition of HCB-induced porphyria by TAO cannot be explained by a diminished formation of the highly reactive TCBQ, since rats treated with a high dose of PCB, which had a several fold higher urinary excretion of PCP and TCHQ compared to a high dose of HCB, did not develop porphyria. Instead, the present study points to the involvement of a putative reactive intermediate in the primary oxidative step in HCB-induced porphyria, since based on paired observations of individual rats, the degree of porphyria was correlated to a high degree with excretion of PCP, whereas correlation of porphyria with early excretion of TCHQ was much weaker. This finding fits well with the fact that the mechanisms of oxidation of HCB to PCP and PCB to PCP are different. Both HCB and PCB were oxidized to PCP and tetrachlorohydroquinone (TCHQ), the reduced analog of TCBQ. Cytochrome P450IIIA1/2 appears to be involved in the conversion of HCB and PCB, since cotreatment of TAO resulted in a strongly diminished urinary excretion of PCP and TCHQ. Treatment with HCB as well as PCB results in disturbances of retinoid and thyroid hormone homeostasis. These effects, which have also been reported after exposure to polychlorinated biphenyls, originate from interference of hydroxylated metabolites (notably PCP) with the plasma thyroxine transport protein, transthyretine, and since this metabolite is formed from both HCB and PCB, this results in the same toxicity for both compounds.
六氯苯（HCB）会引发一系列广泛的效应，包括血红素合成紊乱（卟啉症）以及甲状腺激素稳态失衡。就其大多数效应而言，母体化合物的生物转化似乎是一个先决条件。本研究旨在评估HCB诱导毒性中氧化代谢产物的相关性，特别关注反应性四氯苯醌（TCBQ）的作用。为此，将HCB的毒性和生物转化与五氯苯（PCB）进行了比较，因为这种化学物质被氧化为与HCB相同的产物，即五氯苯酚（PCP）和TCBQ。雌性Wistar大鼠连续13周食用含有不同剂量水平HCB或PCB的饲料，同时或不同时接受三乙酰竹桃霉素（TAO，一种细胞色素P450IIIA1/2的选择性抑制剂）的联合处理。用HCB（高剂量）处理的大鼠从第4周开始尿卟啉水平显著升高，并且在研究结束时肝脏中有大量卟啉蓄积。接受HCB和TAO联合处理的大鼠，其尿卟啉排泄和肝脏卟啉蓄积均受到极大抑制。然而，TAO对HCB诱导的卟啉症的抑制作用不能用高反应性TCBQ生成减少来解释，因为用高剂量PCB处理的大鼠，其PCP和TCHQ的尿排泄量比高剂量HCB高出数倍，但并未出现卟啉症。相反，本研究指出在HCB诱导的卟啉症的初级氧化步骤中存在一种假定的反应性中间体，因为基于对个体大鼠的配对观察，卟啉症的程度与PCP的排泄高度相关，而卟啉症与TCHQ早期排泄的相关性则弱得多。这一发现与HCB氧化为PCP和PCB氧化为PCP的机制不同这一事实非常吻合。HCB和PCB均被氧化为PCP和四氯对苯二酚（TCHQ，TCBQ的还原类似物）。细胞色素P450IIIA1/2似乎参与了HCB和PCB的转化，因为TAO联合处理导致PCP和TCHQ的尿排泄量大幅减少。用HCB以及PCB处理均会导致视黄醇和甲状腺激素稳态失衡。这些效应在接触多氯联苯后也有报道，其源于羟基化代谢产物（特别是PCP）对血浆甲状腺素转运蛋白转甲状腺素蛋白的干扰，并且由于这种代谢产物由HCB和PCB两者形成，这导致两种化合物具有相同的毒性。
