Oxidative metabolism enhances the cytotoxic and genotoxic properties of the soy isoflavone daidzein

Abstract

These data indicate that oxidative metabolism of DAI generates metabolites with genotoxic properties where interference with topoisomerase II might play a role.

Regioselectivity-driven evolution of CYP102D1 for improved synthesis of 3′-ortho-dihydroxyisoflavone

“…Interestingly, the anti-oxidant activity of daidzein can be enhanced dramatically by the addition of more hydroxyl groups or ortho-dihydroxylated moieties to either the A-or B-ring, consistent with the general rules of isoflavonoid structure-antioxidant activity relationships [8,[10][11][12][13]. For example, ortho-dihydroxylated derivatives of daidzein have been shown to have significantly higher anti-cancer, anti-inflammation, and anti-oxidation activities than daidzein itself [14][15][16][17]. Among the ortho-dihydoxylated molecules [i.e., 3 ,4 ,7-trihydroxyisoflavone (3 -OHD), 4 ,6,7-trihydroxyisoflavone (6-OHD), and 4 ,7,8-trihydroxyisoflavone (8-OHD)], 3 -OHD, a hydroxyl derivative with an OH group at C3 , has shown the highest superoxide radical scavenging activity and tyrosinase/melanin inhibitory activity.…”

Impact of Oxidative Metabolism on the Cytotoxic and Genotoxic Potential of Genistein in Human Colon Cancer Cells

“…Until now, little is known about the biological activity of these metabolites, but first studies indicate a potential modulation of the bioactivity of the parent compounds. For example, 6‐OH‐DAI was shown to act as a potent TOP inhibitor, whereas the parent compound DAI is considered inactive in that regard . Another metabolite, 3′‐OH‐GEN, was reported to inhibit angiogenesis in vivo, albeit to a lesser extent than GEN .…”

“…As this metabolite, in contrast to GEN and 3′‐OH‐GEN, did not increase the amount of cleavage complexes in HT‐29 cells (Figure ), the results might indicate that 6‐OH‐GEN acts as a catalytic inhibitor of TOPII. Previously, 6‐OH‐DAI, an oxidative metabolite of daidzein, was also reported to also act as a catalytic inhibitor of TOPII . However, 6‐OH‐GEN was also found in much lower intracellular concentrations after a 1 h incubation than GEN and 3′‐OH‐GEN (Figure ), which might be caused by its seemingly greater susceptibility to glucuronidation and sulfation and the consequently enhanced excretion from the cells.…”

“…Uptake analysis was performed as previously described in detail. [25] Briefly, HT-29 cells were incubated with the test substances for 1 h, harvested, and lysed. Protein concentration of the lysates was determined according to the method of Bradford.…”

“…For example, 6-OH-DAI was shown to act as a potent TOP inhibitor, whereas the parent compound DAI is considered inactive in that regard. [14] Another metabolite, 3 -OH-GEN, was reported to inhibit angiogenesis in vivo, albeit to a lesser extent than GEN. [15] The same metabolite was shown to possess antioxidative properties in cell-free oxygen radical absorbance capacity (ORAC) and LDL oxidation assays, [16] but on the other hand caused oxidative DNA damages in MCF-7 cells, [17] which suggests a pro-oxidative mechanism not assessed by the former methods. Furthermore, 3 -OH-GEN was reported to be similar potent as GEN in binding to both isoforms of the estrogen receptor (ER).…”