Paigen B, Holmes P A, Morrow A, Mitchell D
Cancer Res. 1986 Jul;46(7):3321-4.
Inbred mouse strains AKXL-38 and AKXL-38a are congenic strains that differ at the Ah locus, a gene which affects the inducibility of the cytochrome P-450 enzymes. The Ah-responsive strain, AKXL-38a, is more susceptible to 3-methylcholanthrene-induced tumors than the Ah-nonresponsive strain, AKXL-38. We previously reported that 3-methylcholanthrene (MC) increased the number and the size of atherosclerotic lesions in a dose-dependent fashion. We now demonstrate that the effect of MC is greater in Ah-responsive mice than in Ah-nonresponsive mice indicating that Ah-responsive mice not only are more susceptible to MC-induced cancer but also are more susceptible to MC-enhanced atherosclerosis. Mice that received atherogenic diet for 14 weeks but no MC had 1.3-1.4 lesions/mouse regardless of genetic type. When mice were treated with MC, the number of lesions increased to 2.1 +/- 0.1 (SE) in Ah-nonresponsive mice, 2.6 +/- 0.2 in Ah-responsive mice, and 2.3 +/- 0.2 in the F1 hybrid. The total area involved in lesions was 9.3-12.6 micron2 in untreated animals. When mice were treated with MC, the total lesion area increased to 23.5 +/- 5.2 micron2 in Ah-nonresponsive mice, to 43.9 +/- 6.6 micron2 in Ah-responsive mice, and to 36.2 +/- 4.8 micron2 in F1 hybrids. Thus MC increased the lesion area in both strains of mice, but the increase was significantly greater in Ah-responsive than in Ah-nonresponsive animals. High density lipoprotein levels were not significantly affected by MC treatment or Ah genotype. In order to determine whether the increased susceptibility to MC-induced atherosclerosis segregated with the Ah gene, AKXL-38 and AKXL-38a mice were mated and the F1 progeny were backcrossed to the Ah-nonresponsive parent. Backcross progeny were tested for Ah genotype by zoxazolamine sleeping time. Measurements of lesions showed that increased susceptibility to MC-enhanced atherosclerosis segregated with the Ah locus.
近交系小鼠AKXL - 38和AKXL - 38a是同源近交系，它们在Ah位点存在差异，Ah基因会影响细胞色素P - 450酶的诱导性。Ah反应型品系AKXL - 38a比Ah无反应型品系AKXL - 38对3 - 甲基胆蒽诱导的肿瘤更敏感。我们之前报道过，3 - 甲基胆蒽（MC）以剂量依赖的方式增加动脉粥样硬化病变的数量和大小。我们现在证明，MC对Ah反应型小鼠的作用比对Ah无反应型小鼠的作用更大，这表明Ah反应型小鼠不仅对MC诱导的癌症更敏感，而且对MC增强的动脉粥样硬化也更敏感。接受致动脉粥样硬化饮食14周但未接受MC处理的小鼠，无论基因类型如何，每只小鼠有1.3 - 1.4个病变。当小鼠接受MC处理时，Ah无反应型小鼠的病变数量增加到2.1±0.1（标准误），Ah反应型小鼠增加到2.6±0.2，F1杂种增加到2.3±0.2。未处理动物的病变总面积为9.3 - 12.6平方微米。当小鼠接受MC处理时，Ah无反应型小鼠的病变总面积增加到23.5±5.2平方微米，Ah反应型小鼠增加到43.9±6.6平方微米，F1杂种增加到36.2±4.8平方微米。因此，MC增加了两种品系小鼠的病变面积，但Ah反应型小鼠的增加幅度明显大于Ah无反应型动物。高密度脂蛋白水平不受MC处理或Ah基因型的显著影响。为了确定对MC诱导的动脉粥样硬化易感性增加是否与Ah基因分离，将AKXL - 38和AKXL - 38a小鼠交配，并将F1后代与Ah无反应型亲本回交。通过乙恶唑胺睡眠时间对回交后代进行Ah基因型检测。病变测量显示，对MC增强的动脉粥样硬化易感性增加与Ah位点分离。
