Inhibition of human cytochrome CYP 1 enzymes by flavonoids of St. John's wort.

CYP 1B1 is involved in metabolizing both polycyclic aromatic hydrocarbons and estradiol to potentially carcinogenic intermediates, and it is also over-expressed in human cancer cells. In order to investigate whether flavonoids could specifically inhibit CYP 1B1, seven flavonoids in St. John's wort and apigenin were screened for their inhibition of recombinant human CYP 1B1 and CYP 1A1. While seven flavonoids (myricetin, apigenin, kaempferol, quercetin, amentoflavone, quercitrin and rutin) were slightly more selective for CYP 1B1 EROD inhibition (K(i)s 0.06-5.96 microM) compared to CYP 1A1 (K(i)s 0.20-1.6 microM) the difference in K(i)s for the P450s were not significantly different. Rutin did not inhibit CYP 1A1 at concentrations up to 10 microM. Kinetic analyses determined that apigenin and amentoflavone were competitive inhibitors of CYP 1B1, while quercetin showed mixed type inhibition. To characterize the inhibition potential of these flavonoids, five were studied further for their ability to inhibit TCDD-induced EROD activity in 22Rv1 human prostate cancer cells. 22Rv1 cells express constitutive and TCDD-inducible CYP 1A1 and CYP 1B1 mRNA. In the cells, the IC(50)s were similar to those measured for the recombinant CYP 1A1 except for amentoflavone. Quercetin (IC(50): 4.1 microM), kaempferol (3.8 microM), myricetin (3.0 microM) and apigenin (3.1 microM) caused significant inhibition of EROD activity whereas amentoflavone did not cause inhibition. Depending on their bioavailability, flavonoids that can selectively inhibit CYP1 enzymes may be useful as chemoprotective agents in prostate cancer prevention.