Heteroactivation of cytochrome P450 1A1 by teas and tea polyphenols

1 We studied 7-ethoxyresorufin deethylase as an index of cytochrome P4501A1 (CYP1A1) activity in liver microsomes from rats pretreated with 3-methylcholanthrene. The enzyme had complex kinetics compatible with a multisite model. 2 At 1 mu m substrate, brewed black, green and white teas had complex effects on enzyme activity consisting of activation at low concentrations and inhibition at higher concentrations. 3 Data fit well to a two-site model that allowed us to determine maximal activation (% increase above control), pEC(50) for activation (g ml(-1)) and pIC(50) for inhibition (g ml(-1)). These parameters were 190 +/- 40, 5.9 +/- 0.1 and 4.51 +/- 0.09 for green tea, 350 +/- 40, 5.43 +/- 0.05 and 5.43 +/- 0.05 for black tea and 230 +/- 80, 5.3 +/- 0.3 and 4.7 +/- 0.2 for white tea, respectively. 4 The effects of the brewed teas were mimicked to different degrees by the green tea polyphenols. Maximal activation, pEC(50) (m) and pIC(50) (M) Were: (-)-epicatechin, 55 +/- 9, 5.4 +/- 0.3, 2 +/- 1; (-)-epicatechin gallate, 160 +/- 60, 6.2 +/- 0.3, 5.28 +/- 0.06; (-)-epigallocatechin 30 +/- 10, 6.5 +/- 0.5, 3.37 +/- 0.08; and (-)-epigallocatechin gallate 130 +/- 40, 6.7 +/- 0.3. 5.0 +/- 0.1. A crude extract of black tea polyphenols inhibited 7-ethoxyresorufin deethylase, but did not cause enzyme activation consistently. 5 Enzyme activation was dependent upon substrate concentration. 6 Heteroactivation of CYP1A1 may partially explain the lack of agreement between biological and epidemiological evidence of a role for tea in cancer prevention.