Mueller Stefan O, Kling Margret, Arifin Firzani Poppy, Mecky Astrid, Duranti Eric, Shields-Botella Jacqueline, Delansorne Remi, Broschard Thomas, Kramer Peter-Jürgen
Institute of Toxicology, Merck KGaA, 64271 Darmstadt, Germany.
Toxicol Lett. 2003 Apr 30;142(1-2):89-101. doi: 10.1016/s0378-4274(03)00016-x.
4-Methylbenzylidene-camphor (4-MBC) is an organic sunscreen that protects against UV radiation and may therefore help in the prevention of skin cancer. Recent results on the estrogenicity of 4-MBC have raised concerns about a potential of 4-MBC to act as an endocrine disruptor. Here, we investigated the direct interaction of 4-MBC with estrogen receptor (ER) alpha and ERbeta in a series of studies including receptor binding, ER transactivation and functional tests in human and rat cells. 4-MBC induced alkaline phosphatase activity, a surrogate marker for estrogenic activity, in human endometrial Ishikawa cells. Interestingly, 4-MBC induced weakly ERalpha and with a higher potency ERbeta mediated transactivation in Ishikawa cells at doses more than 1 microM, but showed no distinct binding affinity to ERalpha or ERbeta. In addition, 4-MBC was an effective antagonist for ERalpha and ERbeta. In an attempt to put 4-MBC's estrogenic activity into perspective we compared binding affinity and potency to activate ER with phyto- and xenoestrogens. 4-MBC showed lower estrogenic potency than genistein, coumestrol, resveratrol, bisphenol A and also camphor. Analysis of a potential metabolic activation of 4-MBC that could account for 4-MBC's more distinct estrogenic effects observed in vivo revealed that no estrogenic metabolites of 4-MBC are formed in primary rat or human hepatocytes. In conclusion, we were able to show that 4-MBC is able to induce ERalpha and ERbeta activity. However, for a hazard assessment of 4-MBC's estrogenic effects, the very high doses of 4-MBC required to elicit the reported effects, its anti-estrogenic properties as well as its low estrogenic potency compared to phytoestrogens and camphor has to be taken into account.
4-甲基亚苄基樟脑（4-MBC）是一种有机防晒剂，可抵御紫外线辐射，因此可能有助于预防皮肤癌。最近关于4-MBC雌激素活性的研究结果引发了人们对其作为内分泌干扰物潜在作用的担忧。在此，我们通过一系列研究，包括受体结合、雌激素受体（ER）反式激活以及在人和大鼠细胞中的功能测试，研究了4-MBC与ERα和ERβ的直接相互作用。4-MBC在人子宫内膜 Ishikawa 细胞中诱导了碱性磷酸酶活性，这是雌激素活性的替代标志物。有趣的是，在剂量超过1 microM时，4-MBC在 Ishikawa 细胞中微弱地诱导了ERα，并且以更高的效力诱导了ERβ介导的反式激活，但对ERα或ERβ没有明显的结合亲和力。此外，4-MBC是ERα和ERβ的有效拮抗剂。为了正确看待4-MBC的雌激素活性，我们将其与植物雌激素和外源性雌激素的结合亲和力及激活ER的效力进行了比较。4-MBC的雌激素效力低于染料木黄酮、香豆雌酚、白藜芦醇、双酚A，也低于樟脑。对4-MBC可能的代谢激活进行分析，以解释在体内观察到的4-MBC更明显的雌激素效应，结果显示在原代大鼠或人肝细胞中未形成4-MBC的雌激素代谢产物。总之，我们能够证明4-MBC能够诱导ERα和ERβ活性。然而，对于4-MBC雌激素效应的危害评估，必须考虑引发所报道效应所需的非常高剂量的4-MBC、其抗雌激素特性以及与植物雌激素和樟脑相比其较低的雌激素效力。
