Lambrecht R W, Sinclair P R, Bement W J, Sinclair J F
Veterans Administration, White River Junction, Vermont 05001.
Toxicol Appl Pharmacol. 1988 Dec;96(3):507-16. doi: 10.1016/0041-008x(88)90010-5.
Uroporphyrin (URO) accumulation caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3,4,3',4'-tetrachlorobiphenyl (TCB) in cultured chick embryo hepatocytes was found to depend on the concentration of the added polyhalogenated aromatic compound, and on either the addition of 5-aminolevulinic acid or the induction of 5-aminolevulinic acid synthase. TCDD alone did not cause more than a slight increase in uroporphyrin, whereas TCB alone caused considerable uroporphyrin accumulation associated with increased 5-aminolevulinic acid synthase activity. However, in the presence of exogenous 5-aminolevulinic acid, TCDD was more potent than TCB in causing uroporphyrin accumulation. The concentrations of TCDD or TCB which maximally induced ethoxyresorufin deethylase activity, an indicator of induced cytochrome P450 activity, were lower than those required for maximal uroporphyrin accumulation. Furthermore, ethoxyresorufin deethylase activity was found to decline at concentrations of TCDD or TCB which caused maximum uroporphyrin accumulation. Pretreatment with 3-methylcholanthrene enhanced uroporphyrin accumulation, whereas addition of inhibitors of cytochrome P450 decreased uroporphyrin accumulation. Uroporphyrin accumulation occurred without a decrease in uroporphyrinogen decarboxylase activity, and was unrelated to the degree of conversion of the polyhalogenated aromatic compounds to water-soluble metabolites. Our results indicate that URO accumulation caused by TCDD and TCB requires two separate actions; (1) induction of cytochrome P450 which occurs at low concentrations of the halogenated chemicals, and (2) increased uroporphyrinogen oxidation which is catalyzed by the induced cytochrome P450 and which occurs at higher concentrations of the halogenated chemicals.
在培养的鸡胚肝细胞中，由2,3,7,8-四氯二苯并对二恶英（TCDD）和3,4,3',4'-四氯联苯（TCB）引起的尿卟啉（URO）积累被发现取决于添加的多卤代芳烃化合物的浓度，以及5-氨基乙酰丙酸的添加或5-氨基乙酰丙酸合酶的诱导。单独的TCDD不会导致尿卟啉有超过轻微的增加，而单独的TCB会导致相当多的尿卟啉积累，并伴有5-氨基乙酰丙酸合酶活性增加。然而，在存在外源性5-氨基乙酰丙酸的情况下，TCDD在导致尿卟啉积累方面比TCB更有效。最大程度诱导乙氧异吩恶唑酮脱乙基酶活性（诱导细胞色素P450活性的指标）的TCDD或TCB浓度低于最大尿卟啉积累所需的浓度。此外，在导致最大尿卟啉积累的TCDD或TCB浓度下，乙氧异吩恶唑酮脱乙基酶活性会下降。用3-甲基胆蒽预处理会增强尿卟啉积累，而添加细胞色素P450抑制剂会降低尿卟啉积累。尿卟啉积累发生时尿卟啉原脱羧酶活性没有降低，并且与多卤代芳烃化合物转化为水溶性代谢物 的程度无关。我们的结果表明，TCDD和TCB引起的URO积累需要两个独立的作用；（1）在低浓度卤代化学物质时发生的细胞色素P450的诱导，以及（2）由诱导的细胞色素P450催化且在较高浓度卤代化学物质时发生的尿卟啉原氧化增加。
