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[Cancer Research 61, 8164-8170, November 15, 2001]
© 2001 American Association for Cancer Research

Carcinogenesis

A New Selective and Potent Inhibitor of Human Cytochrome P450 1B1 and Its Application to Antimutagenesis1

Young-Jin Chun2, Sanghee Kim, Donghak Kim, Sang-Kwang Lee and F. Peter Guengerich2

College of Pharmacy, Chungang University, Seoul 156-756, Korea [Y-J. C., S-K. L.]; Natural Product Research Institute, Seoul National University, Seoul 110-460, Korea [S. K.]; and Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 [D. K., F. P. G.]

Human cytochrome P450 (P450) 1B1 is found mainly in extrahepatic tissues and is overexpressed in a variety of human tumors. Metabolic activation of 17ß-estradiol (E2) to 4-hydroxy E2 by P450 1B1 has been postulated to be a factor in mammary carcinogenesis. The inhibition of recombinant human P450 1B1 by 2,4,3',5'-tetramethoxystilbene (TMS) was investigated using either bacterial membranes from a human P450/NADPH-P450 reductase bicistronic expression system or using purified enzymes. TMS showed potent and selective inhibition of the ethoxyresorufin O-deethylation (EROD) activity of P450 1B1 with an IC50 value of 6 nM. TMS exhibited 50-fold selectivity for P450 1B1 over P450 1A1 (IC50 = 300 nM) and 500-fold selectivity for P450 1B1 over P450 1A2 (IC50 = 3 µM). The inhibitory effects of TMS on EROD activity of human liver microsomes were determined. TMS inhibited EROD activity of human liver microsomes at the same concentration as with recombinant human P450 1A2. TMS also strongly inhibited 4- and 2-hydroxylation of E2 by P450 1B1-expressing membranes or purified P450 1B1. TMS was a competitive inhibitor of P450 1B1 with a Ki of 3 nM. The inhibition by TMS was not mechanism-based, and the loss of activity was not blocked by the trapping agents glutathione, N-acetylcysteine, or dithiothreitol. Using purified histidine-tagged P450 1B1, the binding kinetic analysis was performed with TMS, yielding a Kd of 3 µM. The activation of 2-amino-3,5-dimethylimidazo[4,5-f]quinoline in an Escherichia coli lac-based mutagenicity tester system containing functional human P450 1B1 was strongly inhibited by TMS. Our results indicate that TMS is a very selective and potent competitive inhibitor of P450 1B1. TMS is selective for inhibiting P450 1B1 among other human P450s including 1A1, 1A2, and 3A4 and warrants consideration as a candidate for preventing mammary tumor formation by E2 in humans.




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Copyright © 2001 by the American Association for Cancer Research.