Department of Surgery (Head and Neck Service), Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Cancer Prev Res (Phila). 2012 Apr;5(4):593-602. doi: 10.1158/1940-6207.CAPR-12-0002. Epub 2012 Feb 28.
The aryl hydrocarbon receptor (AhR), a ligand-activated member of the basic helix-loop-helix family of transcription factors, plays a significant role in polycyclic aromatic hydrocarbon (PAH)-induced carcinogenesis. In the upper aerodigestive tract of humans, tobacco smoke, a source of PAHs, activates the AhR leading to increased expression of CYP1A1 and CYP1B1, which encode proteins that convert PAHs to genotoxic metabolites. Inhibitors of Hsp90 ATPase cause a rapid decrease in levels of AhR, an Hsp90 client protein, and thereby block PAH-mediated induction of CYP1A1 and CYP1B1. The main objective of this study was to determine whether Zyflamend, a polyherbal preparation, suppressed PAH-mediated induction of CYP1A1 and CYP1B1 and inhibited DNA adduct formation and mutagenesis. We also investigated whether carnosol, one of multiple phenolic antioxidants in Zyflamend, had similar inhibitory effects. Treatment of cell lines derived from oral leukoplakia (MSK-Leuk1) and skin (HaCaT) with benzo[a]pyrene (B[a]P), a prototypic PAH, induced CYP1A1 and CYP1B1 transcription, resulting in enhanced levels of message and protein. Both Zyflamend and carnosol suppressed these effects of B[a]P. Notably, both Zyflamend and carnosol inhibited Hsp90 ATPase activity and caused a rapid reduction in AhR levels. The formation of B[a]P-induced DNA adducts and mutagenesis was also inhibited by Zyflamend and carnosol. Collectively, these results show that Zyflamend and carnosol inhibit Hsp90 ATPase leading to reduced levels of AhR, suppression of B[a]P-mediated induction of CYP1A1 and CYP1B1, and inhibition of mutagenesis. Carnosol-mediated inhibition of Hsp90 ATPase activity can help explain the chemopreventive activity of herbs such as Rosemary, which contain this phenolic antioxidant.
芳香烃受体（AhR）是碱性螺旋-环-螺旋家族转录因子的配体激活成员，在多环芳烃（PAH）诱导的致癌作用中发挥重要作用。在人类上呼吸道，烟草烟雾是 PAHs 的来源，激活 AhR 导致 CYP1A1 和 CYP1B1 的表达增加，这两种蛋白编码将 PAHs 转化为遗传毒性代谢物的蛋白质。Hsp90 ATPase 的抑制剂会导致 AhR（Hsp90 的客户蛋白）水平迅速下降，从而阻断 PAH 介导的 CYP1A1 和 CYP1B1 的诱导。本研究的主要目的是确定复方草药制剂 Zyflamend 是否抑制 PAH 介导的 CYP1A1 和 CYP1B1 的诱导，并抑制 DNA 加合物形成和致突变作用。我们还研究了 Zyflamend 中多种酚类抗氧化剂之一的 carnosol 是否具有类似的抑制作用。用苯并[a]芘（B[a]P）处理源自口腔白斑（MSK-Leuk1）和皮肤（HaCaT）的细胞系，诱导 CYP1A1 和 CYP1B1 转录，导致 mRNA 和蛋白质水平升高。Zyflamend 和 carnosol 均抑制了 B[a]P 的这些作用。值得注意的是，Zyflamend 和 carnosol 均抑制 Hsp90 ATPase 活性并导致 AhR 水平迅速降低。B[a]P 诱导的 DNA 加合物的形成和致突变作用也被 Zyflamend 和 carnosol 抑制。总的来说，这些结果表明 Zyflamend 和 carnosol 抑制 Hsp90 ATPase，导致 AhR 水平降低，抑制 B[a]P 介导的 CYP1A1 和 CYP1B1 的诱导，并抑制致突变作用。Carnosol 介导的 Hsp90 ATPase 活性抑制可以帮助解释含有这种酚类抗氧化剂的草药如迷迭香的化学预防活性。
