Chan Ho Yee, Leung Lai K
Department of Biochemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
Br J Nutr. 2003 Aug;90(2):457-65. doi: 10.1079/bjn2003913.
Epidemiological studies indicate that Asian women have a lower breast cancer incidence compared with their counterparts in the West, and the difference has been related to soya consumption. Animal studies have suggested that soya may prevent dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis in the breast. In the present study a cell culture model was developed to address the effect of soya isoflavones on the DMBA-induced DNA damage. DMBA is metabolized into a DNA-attacking moiety by two phase I cytochrome P450 (CYP) enzymes CYP1A1 and CYP1B1. DNA mutation caused by this genotoxic agent is a crucial step in cancer initiation. Substances that interfere with the CYP1 enzyme activities can affect the initiation. In the present study, genistein was found to be an effective inhibitor of recombinant human CYP1A1 and CYP1B1 with Ki of 15.35 and 0.68 micromol/l. The other soya isoflavone daidzein, on the other hand, did not demonstrate any significant inhibition of the enzyme activities. At the transcriptional level, DMBA induced the CYP1 enzyme expressions by stimulating the xenobiotic response element (XRE)-dependent transactivation pathway. When genistein (25 micromol/l) was co-administered with DMBA, the XRE-Luc activity the CYP1 mRNA abundances were significantly suppressed. The present study illustrated that the soya isoflavone genistein, but not daidzein, protected against DMBA genotoxicity.
流行病学研究表明，与西方女性相比，亚洲女性的乳腺癌发病率较低，这种差异与大豆摄入量有关。动物研究表明，大豆可能预防二甲基苯并[a]蒽（DMBA）诱导的乳腺致癌作用。在本研究中，建立了一种细胞培养模型来研究大豆异黄酮对DMBA诱导的DNA损伤的影响。DMBA通过两种I相细胞色素P450（CYP）酶CYP1A1和CYP1B1代谢为一种攻击DNA的部分。这种遗传毒性剂引起的DNA突变是癌症发生的关键步骤。干扰CYP1酶活性的物质会影响癌症的起始。在本研究中，发现染料木黄酮是重组人CYP1A1和CYP1B1的有效抑制剂，其抑制常数（Ki）分别为15.35和0.68微摩尔/升。另一方面，另一种大豆异黄酮黄豆苷元未表现出对酶活性的任何显著抑制作用。在转录水平上，DMBA通过刺激外源性反应元件（XRE）依赖性反式激活途径诱导CYP1酶表达。当染料木黄酮（25微摩尔/升）与DMBA共同给药时，XRE荧光素酶活性和CYP1 mRNA丰度均显著受到抑制。本研究表明，大豆异黄酮染料木黄酮而非黄豆苷元可预防DMBA的遗传毒性。
