Schmidt U, Machemer L
Fachbereich Toxikologie, Bayer AG, Wuppertal, FR Germany.
Food Addit Contam. 1989;6 Suppl 1:S41-55. doi: 10.1080/02652038909373757.
In toxicological studies, the test compound FOE 3440 A, a [(3,5-dichloro-2-pyridyl)oxy]phenoxypropanoate with herbicidal properties, produced a severe increase in weight and an intensive induction of monoxygenases activity in the mouse, but not in the rat. Comparative subacute studies were performed with oral administration of 0, 5, 20 and, in some instances, 80 mg kg-1 body weight to mice, rats, hamsters, dogs and rhesus monkeys. Liver enzyme activities were measured. The evaluation of the enzyme activity results showed an unusually severe dose-related induction of the monooxygenases [7-ethoxycoumarin-O-deethylase (EOD), 7-ethoxyresorufin-O-deethylase (EOR) and aldrin epoxidase (ALD)] in the mouse and a much weaker reaction in the other species tested. This exceptional position of the mouse was also demonstrated in vitro by a cytochrome P-450 interaction (inhibition of ALD). The primary metabolite of FOE 3440 A produced a distinct inhibition of the ALD in mice liver microsomes. There were no interactions for the other species. Tests for this cytochrome P-450 interaction using microsomes from three different human livers gave no indications of an inhibition in any case. The 'phenoxypropanoic acid' moiety of FOE 3440 A is structurally similar to the pharmaceutical clofibrate, a familiar model substance for peroxisome proliferation. In order to answer the question of whether peroxisome proliferation is the second mechanism for affecting liver, the carnitine acetyl transferase activity (CA-T), a marker enzyme for peroxisome proliferation, was determined in all liver samples from the comparative species studies. The most striking result of the measurement of CA-T activity was the very large increase in the male rat in the low dose group of 5 mg kg-1. Lesser increases in the CA-T activity were measured in the female rat, the mouse, and also in the 20 mg kg-1 group of the hamster. By comparison, the changes of the activity in dog and monkey were very small. Comparative studies in mouse and hamster using a model substance described in the literature (1,4-bis[2-(3,5-dichloropyridyloxy]-benzene (TCPOBOP] indicated that the '3,5-dichloropyridyloxy' moiety of FOE 3440 A is responsible for the induction of the monooxygenases in the mouse and the 'phenoxypropanoic acid' moiety for the peroxisome proliferation in rodents.
在毒理学研究中，受试化合物FOE 3440 A，一种具有除草特性的[(3,5-二氯-2-吡啶基)氧基]苯氧基丙酸酯，在小鼠中导致体重显著增加并强烈诱导单加氧酶活性，但在大鼠中未出现此现象。对小鼠、大鼠、仓鼠、狗和恒河猴进行了比较亚急性研究，口服给予剂量为0、5、20 mg/kg体重，在某些情况下为80 mg/kg体重。测量了肝脏酶活性。对酶活性结果的评估显示，单加氧酶[7-乙氧基香豆素-O-脱乙基酶(EOD)、7-乙氧基试卤灵-O-脱乙基酶(EOR)和艾氏剂环氧化酶(ALD)]在小鼠中呈现出异常严重的剂量相关诱导，而在其他受试物种中反应则弱得多。小鼠的这种特殊情况在体外通过细胞色素P-450相互作用(对ALD的抑制)也得到了证实。FOE 3440 A的主要代谢产物对小鼠肝脏微粒体中的ALD产生了明显抑制。其他物种未出现相互作用。使用来自三种不同人类肝脏的微粒体进行的这种细胞色素P-450相互作用测试在任何情况下均未显示出抑制迹象。FOE 3440 A的“苯氧基丙酸”部分在结构上与药物氯贝丁酯相似，氯贝丁酯是过氧化物酶体增殖的常见模型物质。为了回答过氧化物酶体增殖是否是影响肝脏的第二种机制这一问题，在比较物种研究的所有肝脏样本中测定了肉碱乙酰转移酶活性(CA-T)，这是过氧化物酶体增殖的标记酶。测量CA-T活性最显著的结果是，在5 mg/kg低剂量组的雄性大鼠中该活性大幅增加。在雌性大鼠、小鼠以及仓鼠20 mg/kg组中，CA-T活性也有较小增加。相比之下，狗和猴的活性变化非常小。使用文献中描述的一种模型物质(1,4-双[2-(3,5-二氯吡啶氧基)]苯(TCPOBOP])对小鼠和仓鼠进行的比较研究表明，FOE 3440 A的“3,5-二氯吡啶氧基”部分导致小鼠中单加氧酶的诱导，而“苯氧基丙酸”部分导致啮齿动物中的过氧化物酶体增殖。
