Hahn M E, Gasiewicz T A, Linko P, Goldstein J A
Environmental Health Sciences Center, University of Rochester School of Medicine and Dentistry, NY 14642.
Biochem J. 1988 Aug 15;254(1):245-54. doi: 10.1042/bj2540245.
The role of the Ah locus in hexachlorobenzene (HCB)-induced porphyria and the possible involvement of P-450 cytochromes P(1)450 and P(3)450 in the pathogenesis of this disease were investigated in two congenic strains of C57BL/6J mice that differ only at this locus. Female B6-Ahb mice (Ah receptor: approximately 30-70 fmol/mg of cytosolic protein) and B6-Ahd mice (Ah receptor: undetectable) were pretreated with iron (500 mg/kg) and then fed a diet containing 0 or 200 p.p.m. of HCB for up to 17 weeks. Mice from the two strains consumed similar amounts of HCB. Urinary excretion of porphyrins was increased after 7 weeks of HCB treatment in B6-Ahb mice, and after 15 weeks was over 200 times greater than that of mice given iron only. In B6-Ahd mice, porphyrin excretion did not begin to increase until after 13 weeks, and after 15 weeks was only six times greater than that of controls. Similar differences were seen in the 15-week hepatic porphyrin concentrations (B6-Ahb: 1110 +/- 393; B6-Ahd: 17.6 +/- 14.5; controls: approximately 0.20 nmol/g). Uroporphyrinogen decarboxylase (EC 4.1.1.37) activity was diminished by 70 and 20% in B6-Ahb B6-Ahd mice respectively after 15 weeks of treatment with HCB. Cytochromes P(1)450 and P(3)450 were measured in hepatic microsomes (microsomal fractions) by radioimmunoassay and immunoblotting, using antisera raised against the orthologous rat isoenzymes P450c and P450d. HCB induced small amounts of a protein recognized by anti-P450c (P(1)450) in B6-Ahd mice, but not in B6-Ahd mice. Relatively large amounts of a protein recognized by anti-P450d (P(3)450) were induced in both strains, but to a somewhat greater extent in the B6-Ahb mice. The hepatic accumulation of HCB at 15 weeks was greater in B6-Ahb than in B6-Ahd mice, in association with elevated hepatic lipid levels in the former strain. The results of this experiment indicate that the Ah locus influences the susceptibility of C57BL/6J mice to HCB-induced porphyria and are consistent with the suggestion that the sustained induction of P(3)450 and/or P(1)450 may be a causative factor in the development of this disease.
在仅在该位点存在差异的两种C57BL/6J小鼠同源近交系中，研究了Ah位点在六氯苯（HCB）诱导的卟啉症中的作用以及细胞色素P(1)450和P(3)450可能参与该疾病发病机制的情况。雌性B6 - Ahb小鼠（Ah受体：约30 - 70 fmol/mg胞质蛋白）和B6 - Ahd小鼠（Ah受体：检测不到）先用铁（500 mg/kg）预处理，然后喂食含0或200 ppm HCB的饲料，持续17周。两个品系的小鼠消耗的HCB量相似。HCB处理7周后，B6 - Ahb小鼠的卟啉尿排泄增加，15周后比仅给予铁的小鼠高出200多倍。在B6 - Ahd小鼠中，卟啉排泄直到13周后才开始增加，15周后仅比对照组高6倍。在15周时肝脏卟啉浓度也有类似差异（B6 - Ahb：1110±393；B6 - Ahd：17.6±14.5；对照组：约0.20 nmol/g）。用HCB处理15周后，B6 - Ahb和B6 - Ahd小鼠的尿卟啉原脱羧酶（EC 4.1.1.37）活性分别降低了70%和20%。通过放射免疫测定和免疫印迹法，使用针对同源大鼠同工酶P450c和P450d产生的抗血清，在肝微粒体（微粒体部分）中测量细胞色素P(1)450和P(3)450。HCB在B6 - Ahd小鼠中诱导产生少量可被抗P450c（P(1)450）识别的蛋白质，但在B6 - Ahd小鼠中未诱导产生。在两个品系中均诱导产生了相对大量可被抗P450d（P(3)450）识别的蛋白质，但在B6 - Ahb小鼠中诱导程度稍大。15周时，B6 - Ahb小鼠肝脏中HCB的蓄积量比B6 - Ahd小鼠更大，且前一品系的肝脏脂质水平升高。该实验结果表明，Ah位点影响C57BL/6J小鼠对HCB诱导的卟啉症的易感性，并且与P(3)450和/或P(1)450的持续诱导可能是该疾病发生的一个致病因素这一观点一致。
