Iba M M, Lang B, Thomas P E, Ghosal A
Department of Pharmacology, Rutgers University-Busch Campus, Piscataway, NJ 08854-0789.
Biochem Pharmacol. 1990 Aug 1;40(3):581-7. doi: 10.1016/0006-2952(90)90559-4.
Administration of a single oral dose (20 mg/kg) of [U-14C]3,3'-dichlorobenzidine to rats resulted in the in vivo covalent binding of the compound to hepatic lipids. More than 70% of the lipid-3,3'-dichlorobenzidine adducts were accounted for in microsomes. Loss of the lipid-bound 3,3'-dichlorobenzidine residues from either total liver or endoplasmic reticulum occurred in at least two phases--an initial fast phase and a terminal slow phase. In vitro studies with hepatic microsomes in the presence of antibodies to specific P450 isozymes and chemical inhibitors to determine the enzymes that activate 3,3'-dichlorobenzidine to the lipid-binding derivative(s) implicated cytochrome P450d. The 3,3'-dichlorobenzidine-bound microsomal lipids were not mutagenic to Salmonella TA98 in the Ames test. The results suggest that adduct formation between 3,3'-dichlorobenzidine and membrane lipids may provide a measure of 3,3'-dichlorobenzidine activation. It is speculated that covalent interaction of the compound with membrane lipids may modify cellular processes, leading to either enhancement or attenuation of carcinogenesis by the chemical.
给大鼠单次口服剂量为20毫克/千克的[U-14C]3,3'-二氯联苯胺，会导致该化合物在体内与肝脏脂质发生共价结合。超过70%的脂质-3,3'-二氯联苯胺加合物存在于微粒体中。无论是在全肝还是内质网中，脂质结合的3,3'-二氯联苯胺残基的损失至少分两个阶段发生——初始的快速阶段和终末的缓慢阶段。在体外实验中，利用针对特定细胞色素P450同工酶的抗体和化学抑制剂处理肝微粒体，以确定激活3,3'-二氯联苯胺生成脂质结合衍生物的酶，结果表明细胞色素P450d参与其中。在艾姆斯试验中，3,3'-二氯联苯胺结合的微粒体脂质对鼠伤寒沙门氏菌TA98没有致突变性。这些结果表明，3,3'-二氯联苯胺与膜脂质之间形成加合物可能是衡量3,3'-二氯联苯胺活化程度的一个指标。据推测，该化合物与膜脂质的共价相互作用可能会改变细胞过程，从而导致该化学物质致癌作用的增强或减弱。
