Glucuronidation of the soyabean isoflavones genistein and daidzein
by human liver is related to levels of UGT1A1 and UGT1A9
activity and alters isoflavone response in the MCF-7
human breast cancer cell line
Louise E. Pritchett
, Kathryn M. Atherton
, Elaine Mutch
, Dianne Ford
Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
School of Clinical and Laboratory Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
Received 30 March 2007; received in revised form 12 September 2007; accepted 18 October 2007
The soyabean isoflavones genistein and daidzein, which may protect against some cancers, cardiovascular disease and bone mineral loss,
undergo substantial Phase 2 metabolism, predominantly glucuronidation. We observed a correlation between rates of metabolism of marker
substrates of specific UGTs and rates of glucuronidation of genistein and daidzein in vitro by a panel of human liver microsomes,
demonstrating that UGT1A1 and UGT1A9, but not UGT1A4, make a major contribution to the metabolism of these isoflavones by human
liver. These findings were substantiated by observations that recombinant human UGT1A1 and UGT1A9, but not UGT1A4, catalysed the
production of the major glucuronides of both genistein and daidzein in vitro. Recombinant human UGT1A8 also metabolised both genistein
and daidzein, whereas UGT1A6 was specific to genistein and UGTs 2B7 and 2B15 were inactive, or only marginally active, with either
isoflavone as substrate. The intestinal isoform UGT1A10 metabolised either both isoflavones or genistein only, depending on the commercial
supplier of the recombinant enzyme, possibly as a result of a difference in amino acid sequence, which we were unable to confirm. Daidzein
(16 μM) increased cell death in the MCF-7 human breast cancer cell line and this effect was reversed by glucuronidation. In view of a
well-characterised functional polymorphism in UGT1A1, these observations may have implications for inter-individual variability in the
potential health-beneficial effects of isoflavone consumption.
© 2008 Elsevier Inc. All rights reserved.
Keywords: Phytoestrogen; Isoflavone; Genistein; Daidzein; MCF-7 cells; UDP-glucuronosyltransferase
The isoflavones are plant polyphenolic compounds of
which the soyabean is a particularly rich source. Some
evidence indicates a range of potential health-beneficial
effects of soyabean and/or isoflavone consumption, includ-
ing protection against cardiovascular disease, bone mineral
loss and various cancers. For example, epidemiological
evidence links the typical Asian diet, which includes a high
content of the isoflavone-rich soyabean and soyabean-
derived products, with lower rates of cardiovascular disease
and osteoporosis-related hip fractures (reviewed in Refs.
[1,2]) and with reduced risk of cancer of the breast, prostate
and bowel (reviewed in Refs. [3–5]). Intervention trials in
human volunteers indicate that beneficial cardiovascular
effects of soyabean consumption may be related to
components other than isoflavones, but beneficial effects
on bone health appear to be attributable to isoflavones [6,7].
The major soyabean isoflavones genistein and daidzein, fed
in combination to rats, reduced the incidence of chemically
induced prostate adenocarcinoma , and mice fed genistein
in the diet, following the removal of primary mammary
tumours, had reduced metastatic lung tumour burden .In
Available online at www.sciencedirect.com
Journal of Nutritional Biochemistry 19 (2008) 739 – 745
Funded by World Cancer Research Fund International (WCRF) and
the Biotechnology and Biological Sciences Research Council (BBSRC)
(studentship to LEP).
Corresponding author. Tel.: +44 191 2225986; fax: +44 191 2227424.
E-mail address: firstname.lastname@example.org (D. Ford).
0955-2863/$ – see front matter © 2008 Elsevier Inc. All rights reserved.