Modulation of P450 enzymes by Cuban natural products rich in polyphenolic compounds in rat hepatocytes

This paper reports cytotoxic effects and changes in the P450 system after exposing rat hepatocytes to four polyphenol-rich products widely used in Cuban traditional medicine (Mangifera indica L. (MSBE), Thalassia testudinum (Tt), Erythroxylum minutifolium and confusum extracts). Effects of mangiferin, the main polyphenol in MSBE, were also evaluated. Cytotoxicity was assayed by the MTT test after exposure of cells to the products (50–1000 μg/mL) for 24 or 72 h. The results showed that 500 μg/mL MSBE was moderately cytotoxic after 72 h, while mangiferin was not. Marked reductions in cell viability were produced by Erythroxylum extracts at concentrations ≥200 μg/mL, whereas only moderate effects were induced by 1000 μg/mL Tt. Seven specific P450 activities were evaluated after 48 h exposure of cells to the products. MSBE reduced phenacetin O-deethylation (POD; CYP1A2) activity in a concentration-dependent manner (IC50 = 190 μg/mL). No decreases were observed in other activities. In contrast, mangiferin produced reductions in five P450 activities: IC50 values of 132, 194, >200, 151 and 137 μg/ml for POD (CYP1A2), midazolam 1′-hydroxylation (M1OH; CYP3A1), diclofenac 4′-hydroxylation (D4OH; CYP2C6), S-mephenytoin 4′-hydroxylation (SM4OH), and chlorzoxazone 6-hydroxyaltion (C6OH; CYP2E1), respectively. E. minutifolium, E. confusum and Tt extracts produced small reductions in SM4OH and C6OH activities, but no significant changes were noted in the other P450 activities. On the other hand, all the products increased the benzyloxyresorufin O-debenzylation (BROD; CYP2B1) activity, with MSBE, mangiferin or E. minutifolium showing the highest effects (about 2-fold over control). Our results showed in vitro effects of these natural products on P450 systems, possibly leading to potential metabolic-based interactions.