Properties of hypolipidemic peroxisome proliferators in the lymphocyte [3H]thymidine and Salmonella mutagenesis assays.
Properties of hypolipidemic peroxisome proliferators in the lymphocyte [3H]thymidine and Salmonella mutagenesis assays.
复制标题
淋巴细胞[3H]胸苷和沙门氏菌诱变试验中降血脂过氧化物酶体增殖物的特性。
作者：
John R. Warren;Vincent F. Simmon;Janardan K. Reddy
摘要 几种降血脂过氧化物酶体增殖剂已在啮齿类动物中表现出致癌活性。目前已对其中六种降血脂药物诱导细胞 DNA 损伤的能力进行了检查。通过改变[ 3 H]胸苷掺入增殖淋巴细胞体外培养物的复制DNA中的速率以及通过沙门氏菌/微粒体测定中的诱变活性来评估对DNA的损伤。在肝 S-9 微粒体制剂存在和不存在的情况下，降血脂药物乙基-α-对氯苯氧基异丁酸酯（氯贝特）、2-甲基-2-[对-（1,2,3,4-四氢-1-萘基）苯氧基]丙酸（萘芬平）、1-甲基-4-哌啶基双（对氯苯氧基）乙酸酯(SaH-42-348)、2-氯-5-(3,5-二甲基哌啶磺酰基)苯甲酸(tibric Acid)、[4-氯-6-(2,3-xylidino)-2-嘧啶硫基]乙酸(Wy-14,643)和[4-氯-6-(2,3-xylidino)-2-嘧啶硫基(N) -β-羟乙基)乙酰胺] (BR-931) 抑制伴刀豆球蛋白 A 刺激的 C57BL/6J 脾淋巴细胞原代培养物中 [ 3 H]胸苷掺入复制 DNA 的速率。然而，通过将药物处理的淋巴细胞在不含降血脂药物的新鲜培养基中孵育3小时，降血脂药物对[ 3 H]-胸苷掺入复制DNA的抑制被逆转。这与用已知的DNA损伤性致癌物甲基亚硝基脲或苯并(a)芘处理的淋巴细胞形成对比，在没有致癌物的处理淋巴细胞的3小时孵育过程中，[ 3 H]胸苷掺入复制DNA的速率逐渐受到抑制。此外，在不存在或存在肝 S-9 微粒体制剂的情况下，使用鼠伤寒沙门氏菌菌株 TA98、TA100、TA1535、TA1537 和 TA1538 对药物氯贝丁酯、奈非诺平、SaH 42-348、Wy-14,643 或 BR-931 进行沙门氏菌/微粒体测定，未检测到诱变活性。因此，淋巴细胞[ 3 H]胸苷和沙门氏菌诱变试验获得的结果表明，无论存在或不存在肝微粒体，降血脂药物都不会与细胞DNA相互作用并损伤细胞DNA。诱变代谢物是否是由降血脂药物诱导的肝过氧化物酶体产生仍有待阐明。
Abstract Several hypolipidemic peroxisome proliferators have demonstrated carcinogenic activity in rodent species. Six of these hypolipidemic drugs have now been examined for their ability to induce damage in cellular DNA. Damage to DNA was evaluated by alteration in rates of [ 3 H]thymidine incorporation into replicating DNA of in vitro cultures of proliferating lymphocytes and by mutagenic activity in the Salmonella /microsome assay. Both in the absence and presence of liver S-9 microsomal preparation, the hypolipidemic drugs ethyl-α- p -chlorophenoxyisobutyrate (clofibrate), 2-methyl-2-[ p -(1,2,3,4-tetrahydro-1-naphthyl)phenoxy]propionic acid (nafenopin), 1-methyl-4-piperidylbis( p -chlorophenoxy)acetate (SaH-42-348), 2-chloro-5-(3,5-dimethylpiperidinosulfonyl)benzoic acid (tibric acid), [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643), and [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio( N -β-hydroxyethyl)acetamide] (BR-931) suppressed the rate of [ 3 H]thymidine incorporation into replicating DNA in primary cultures of concanavalin A-stimulated C57BL/6J splenic lymphocytes. However, inhibition by hypolipidemic drugs of [ 3 H]-thymidine incorporation into replicating DNA was reversed by incubation of drug-treated lymphocytes for 3 hr in fresh culture medium without hypolipidemic drug. This was in contrast to lymphocytes treated with the known DNA-damaging carcinogens methylnitrosourea or benzo( a )pyrene, in which the rate of [ 3 H]thymidine incorporation into replicating DNA was increasingly suppressed during 3-hr incubation of treated lymphocytes without carcinogen. Furthermore, no mutagenic activity was detected in the Salmonella /microsome assay using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538 for the drugs clofibrate, nafenopin, SaH 42-348, Wy-14,643, or BR-931 either in the absence or presence of liver S-9 microsomal preparation. Results obtained with the lymphocyte [ 3 H]thymidine and the Salmonella mutagenesis assays therefore suggest that the hypolipidemic drugs either in the absence or presence of liver microsomes do not interact with and damage cellular DNA. Whether mutagenic metabolites are generated by hypolipidemic drug-induced liver peroxisomes remains to be elucidated.