Kafafi S A, Afeefy H Y, Ali A H, Said H K, Abd-Elazem I S, Kafafi A G
Department of Environmental Health Sciences, Johns Hopkins University, School of Hygiene and Public Health, Baltimore, MD 21205.
Carcinogenesis. 1993 Oct;14(10):2063-71. doi: 10.1093/carcin/14.10.2063.
Polychlorinated biphenyls (PCBs) are nonplanar aromatic xenobiotics that are not structurally related to polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs), yet, some PCBs are potent ligands for the aryl hydrocarbon receptor (AhR), active inducers of aryl hydrocarbon hydroxylase (AHH) and 7-ethoxyresorufin O-deethylase (EROD), and elicit toxicological responses in animals similar to PCDDs and PCDFs. We report new methodologies for quantifying the affinities of PCBs for AhR and corresponding potencies as AHH and EROD inducers. The models show that lipophilicities, electron affinities, entropies and electronic energy gaps of PCBs are key physicochemical properties controlling their AhR, AHH and EROD activities. Using 3,3',4,4'-tetrachlorobiphenyl (TCB) as the reference compound, it is shown that PCBs having higher electron affinities, lower lipophilicities and entropies than TCB are potent ligands for rat hepatic AhR. In addition, the congeners having higher binding affinities to AhR and smaller energy gaps than TCB are potent AHH and EROD inducers in rat hepatoma cells in culture. The reported models qualitatively explain and quantify AhR, AHH and EROD activities of all 209-PCBs and related xenobiotics, e.g. PCDDs and PCDFs. Furthermore, we demonstrated that AhR and AHH activities of PCBs relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin correlate with corresponding in vivo relative toxicities in animals as well as assigned toxic equivalency factors. The reported methodologies are likely to be useful for identifying potentially toxic aromatic xenobiotics in mammals, and minimizing the need for animal testing.
多氯联苯（PCBs）是一类非平面芳香族外源性物质，其结构与多氯二苯并对二恶英（PCDDs）和二苯并呋喃（PCDFs）无关。然而，一些多氯联苯是芳烃受体（AhR）的有效配体，是芳烃羟化酶（AHH）和7-乙氧基异吩恶唑酮O-脱乙基酶（EROD）的活性诱导剂，并在动物中引发与多氯二苯并对二恶英和多氯二苯并呋喃类似的毒理学反应。我们报告了用于量化多氯联苯对AhR的亲和力以及作为AHH和EROD诱导剂的相应效力的新方法。模型表明，多氯联苯的亲脂性、电子亲和力、熵和电子能隙是控制其AhR、AHH和EROD活性的关键物理化学性质。以3,3',4,4'-四氯联苯（TCB）作为参考化合物，结果表明，与TCB相比，具有更高电子亲和力、更低亲脂性和熵的多氯联苯是大鼠肝脏AhR的有效配体。此外，与TCB相比，对AhR具有更高结合亲和力和更小能隙的同系物是培养的大鼠肝癌细胞中有效的AHH和EROD诱导剂。所报告的模型定性地解释并量化了所有209种多氯联苯及相关外源性物质（如多氯二苯并对二恶英和多氯二苯并呋喃）的AhR、AHH和EROD活性。此外，我们证明了多氯联苯相对于2,3,7,8-四氯二苯并对二恶英的AhR和AHH活性与动物体内相应的相对毒性以及指定的毒性当量因子相关。所报告的方法可能有助于识别哺乳动物中潜在有毒的芳香族外源性物质，并尽量减少动物试验的需求。
