REGULATION OF CYP1A1 BY INDOLO[3,2-B]CARBAZOLE IN MURINE HEPATOMA-CELLS

To determine the basis for unexpected differences in CYP1A1 inducing p otencies and efficacies for the diet-derived indole derivative, indolo [3,2-b]carbazole (ICZ) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), we conducted a systematic analysis of events involved in the induced expression of CYP1A1 in murine hepatoma-derived cell lines (Hepa-1), I n contrast to the effects of TCDD, induction kinetics and CYP1A1 mRNA half-life were dependent on ICZ concentration, and the response from l ow doses of inducer was transient due to rapid clearance of ICZ, TCDD and ICZ produced the same maximum response (i.e. equal efficacies) fro m a TCDD-responsive CAT reporter construct in Hepa-1 cells, When measu red by the immediate responses associated with CYP1A1 expression, incl uding cellular uptake of inducer, receptor transformation and binding to DRE (gel mobility shift assay), initiation of transcription (nuclea r run-on assay), and short-term accumulation of mRNA (Northern blot as say), ICZ also exhibited an efficacy equal to that of TCDD and a poten cy that corresponds to its receptor affinity, ICZ is a potent and sele ctive noncompetitive inhibitor of ethoxyresorufin O-deethylase activit y (K-i = 1.5 nM). Taken together these results indicate that ICZ is a bifunctional modulator of CYP1A1 expression with intrinsic efficacy eq ual to that of TCDD.