Novel quassinoid from Jamaican Castela macrophylla blocks induction of cytochrome P450 1 enzymes and luciferase genes

In this study we investigated the potential for a novel quassinoid, glaucarubulone-15-O-β-D-glucopyranoside (Gg) isolated from the endemic Jamaican Castela macrophylla plant to inhibit cytochromes P450 (CYPs), in particular CYP1A1 and CYP1B1 enzymes, known to convert polyaromatic hydrocarbons (PAHs) into carcinogenic metabolites. Gg attenuated by nearly 70-fold, the ability of PAH, benzo-a-pyrene(B[a]P) to induce CYP1A gene expression in MCF-7 breast cancer cells as determined by real-time RT-PCR. Gg was also shown to directly inhibit the enzyme activity of human CYP1A1 and CYP1B1 enzymes (IC₅₀, 6.93 ± 0.31µM and 9.17 ± 0.91µM respectively) according to non-competitive kinetics. Given the ability of Gg to block the induction of phase I gene expression, we investigated its effects on antioxidant response element (ARE)-dependent induction by crude acai berry fractions. Where acai_92 H at 50 µg/mL caused an approximate five- to seven-fold induction of luciferase gene expression, the inclusion of Gg reduced the induction to below two-fold over the entire range of concentrations, and at 250 nM Gg, complete loss of induction was observed. Taken together, these data suggest that the plant isolate Gg may be an interesting candidate to provide insights into mechanisms of cellular transcription.