A potential protective mechanism of soya isoflavones against 7,12-dimethylbenz[a]anthracene tumour initiation.
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.
Chan
Ho Yee
HY
Department of Biochemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
Leung
Lai K
LK
D015127:9,10-Dimethyl-1,2-benzanthracene; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000032:analysis; D001943:Breast Neoplasms / Q000517:prevention & control*; D002273:Carcinogens; D019363:Cytochrome P-450 CYP1A1 / Q000032:analysis; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D004249:DNA Damage / Q000187:drug effects; D005260:Female; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007529:Isoflavones / Q000627:therapeutic use*; D008156:Luciferases / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D013025:Glycine max; D014407:Tumor Cells, Cultured
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D007529:Isoflavones; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D015127:9,10-Dimethyl-1,2-benzanthracene; D019833:Genistein; D008156:Luciferases; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1