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St. John’s Wort Extracts and Some of Their Constituents Potently Inhibit Ultimate Carcinogen Formation from Benzo[a]pyrene-7,8-Dihydrodiol by Human CYP1A1

Institute of Clinical Pharmacology, University Medical Center Charité, Humboldt University of Berlin, Berlin, Germany

Commercially available St. John’s wort (Hypericum perforatum) preparations and some of their main constituents (hypericin, pseudohypericin, hyperforin, rutin, and quercetin) were examined for their potential to inhibit carcinogen activation by human cytochrome P450 1A1 (CYP1A1). We used a reconstituted system consisting of purified human CYP1A1, purified human NADPH-cytochrome P450 reductase, and dilaurylphosphatidylcholine as lipid component. St. John’s wort extracts potently inhibited CYP1A1-catalyzed (±)-trans-7,8-dihydro-7,8-dihydroxy-benzo(a)pyrene (7,8-diol-B[a]P) epoxidation, the terminal reaction leading to the ultimate carcinogenic product (±)-B[a]P-r-7,t-8-dihydrodiol-t-9,10-epoxide (diolepoxide 2). All constituents, except rutin, were shown to possess strong inhibitory potencies toward diolepoxide 2 formation from 7,8-diol-B[a]P, with IC₅₀ values of 0.5 µM (hypericin), 1.2 µM (hyperforin), 1.5 µM (quercetin), and 8 µM (pseudohypericin), respectively. Preincubation experiments revealed that their action was not mechanism based. Inhibition kinetics studies showed the anthrodianthrone compound hypericin to be a noncompetitive inhibitor, with a K_i value of 0.6 µM, and the phloroglucinol hyperforin to be a competitive inhibitor, with a K_i value of 1.1 µM. When the effects on NADPH-P450 reductase activity were investigated, all constituents of St. John’s wort studied turned out to be rather ineffective inhibitors; quercetin was the only exception, with an IC₅₀ value of 20 µM. These in vitro data indicate that St. John’s wort extracts and some of their constituents potently inhibit the major human procarcinogen-activating enzyme CYP1A1.