Smith A G, Francis J E, Kay S J, Greig J B, Stewart F P
Biochem J. 1986 Sep 15;238(3):871-8. doi: 10.1042/bj2380871.
Porphyria was induced in C57BL/10 mice with iron overload by a single oral dose (100 mg/kg) of hexachlorobenzene (HCB). Within 2 weeks hepatic uroporphyrinogen decarboxylase (EC 4.1.1.37) was inhibited, reaching a maximum (greater than 95%) at 6-8 weeks. There was no recovery by 14 weeks, despite a fall in liver HCB concentrations to only 6% of the day-3 value. The major rise in hepatic porphyrin levels occurred after 4 weeks and secondary inhibition of uroporphyrinogen synthase (EC 4.2.1.75) was inferred from the progressively greater proportion of uroporphyrin I present relative to the III isomer. Plasma alanine aminotransferase (EC 2.6.1.2) activity was also elevated. Although, in further studies, total microsomal cytochrome P-450 content and ethoxyphenoxazone de-ethylase activity reached a peak a few days after dosing and had declined significantly at the time of maximum inhibition of the decarboxylase, additional treatment of HCB-dosed mice with a cytochrome P1-450 inducer, beta-naphthoflavone, enhanced the inhibition, whereas piperonyl butoxide, an inhibitor of cytochrome P-450, partially protected. Uroporphyrinogen decarboxylase was not radiolabelled in vivo by [14C]HCB. There was no major difference in the ability to hydroxylate HCB between hepatic microsomes from induced C57BL/10 mice and those from the insensitive DBA/2 strain. By contrast, lipid peroxidation, in the presence of NADPH, was 8-fold greater in control C57BL/10 microsomes than in DBA/2 microsomes and was stimulated by iron treatment (although not by HCB). The results suggest that the inhibition of hepatic uroporphyrinogen decarboxylase is unlikely to be due to a direct effect of a metabolite of HCB but to another process requiring a specific cytochrome P-450 isoenzyme and an unknown iron species.
通过单次口服剂量（100毫克/千克）的六氯苯（HCB）在铁过载的C57BL/10小鼠中诱导产生卟啉症。在2周内，肝脏尿卟啉原脱羧酶（EC 4.1.1.37）受到抑制，在6-8周时达到最大值（大于95%）。到14周时仍未恢复，尽管肝脏中HCB浓度降至第3天值的仅6%。肝脏卟啉水平的主要升高发生在4周后，并且从尿卟啉I相对于III异构体呈现出的逐渐增加的比例推断出尿卟啉原合酶（EC 4.2.1.75）受到继发性抑制。血浆丙氨酸转氨酶（EC 2.6.1.2）活性也升高。尽管在进一步的研究中，总微粒体细胞色素P-450含量和乙氧苯恶唑酮脱乙基酶活性在给药后几天达到峰值，并且在脱羧酶最大抑制时已显著下降，但用细胞色素P1-450诱导剂β-萘黄酮对HCB给药小鼠进行额外处理会增强抑制作用，而细胞色素P-450抑制剂胡椒基丁醚则有部分保护作用。尿卟啉原脱羧酶在体内未被[14C]HCB放射性标记。诱导的C57BL/10小鼠肝脏微粒体与不敏感的DBA/2品系肝脏微粒体在HCB羟基化能力上没有主要差异。相比之下，在存在NADPH的情况下，对照C57BL/10微粒体中的脂质过氧化比DBA/2微粒体高8倍，并且受到铁处理的刺激（尽管不受HCB刺激）。结果表明，肝脏尿卟啉原脱羧酶的抑制不太可能是由于HCB代谢产物的直接作用，而是由于另一个需要特定细胞色素P-450同工酶和未知铁物种的过程。
