Metabolism of the
isoflavones daidzein and
genistein, which may protect against some
cancers, was studied using human liver microsomes and recombinant CYP
isoforms. The detection of three, more polar metabolites of each
isoflavone by RP-HPLC required
NADPH, consistent with CYP-mediated metabolism. For different liver preparations, metabolite generation from
daidzein showed a significant linear correlation with metabolite generation from
genistein, indicating metabolism by the same CYP(s). The lowest rate of metabolism of both
isoflavones was by the preparation with the lowest
CYP1A2 activity. Metabolite peak areas were substantially and significantly reduced by the
CYP1A2 inhibitor
furafylline and to a lesser extent by the
CYP2E1 inhibitor
4-methylpyrazole. Recombinant
CYP1A2, but not
CYP2E1, generated the metabolites of
daidzein and
genistein and recombinant
CYP1A1 and CYP1B1, expressed at sites including the breast and prostate, were also active. The effects of two CYP-derived metabolites of
daidzein,
6,7,4'-trihydroxyisoflavone and
7,3',4'-trihydroxyisoflavone, were studied in the MCF-7 human
breast cancer cell line at a concentration (50 microM) at which
daidzein induces an antiproliferative response.
7,3',4'-Trihydroxyisoflavone reduced total cell numbers to a greater extent than
6,7,4'-trihydroxyisoflavone or
daidzein and increased cell death. Together, these data demonstrate proof of principle that CYP-mediated metabolism of
daidzein can be an activation pathway. We conclude that
CYP1A2 makes the major contribution to the hepatic metabolism of both
daidzein and
genistein and along with metabolism at sites of
hormone-dependent tumours may enhance a
cancer-protective effect of
daidzein if sufficiently high concentrations are reached in target tissues.