Recent studies have demonstrated
cytochrome P450 CYP1-mediated metabolism and CYP1-enzyme induction by naturally occurring
flavonoids in
cancer cell line models. The arising metabolites often exhibit higher activity than the parent compound. In the present study we investigated the CYP1-mediated metabolism of the citrus polymethoxyflavone
nobiletin by recombinant
CYP1 enzymes and MCF7 breast
adenocarcinoma cells. Incubation of
nobiletin in MCF7 cells produced one main metabolite (NM1) resulting from O-demethylation in either A or B rings of the
flavone moiety. Among the three CYP1
isoforms,
CYP1A1 exhibited the highest rate of metabolism of
nobiletin in recombinant CYP microsomal
enzymes. The intracellular CYP1-mediated bioconversion of the
flavone was reduced in the presence of the
CYP1A1 and CYP1B1-selective inhibitors α-napthoflavone and
acacetin. In addition
nobiletin induced CYP1
enzyme activity,
CYP1A1 protein and CYP1B1
mRNA levels in MCF7 cells at a concentration dependent manner. MTT assays in MCF7 cells further revealed that
nobiletin exhibited significantly lower IC50 (44 μM) compared to cells treated with
nobiletin and
CYP1A1 inhibitor (69 μM). FACS analysis demonstrated cell a cycle block at G1 phase that was attenuated in the presence of
CYP1A1 inhibitor. Taken together the data suggests that the dietary
flavonoid nobiletin induces its own metabolism and in turn enhances its
cytostatic effect in MCF7 breast
adenocarcinoma cells, via
CYP1A1 and CYP1B1 upregulation.