Phase 2 drug-metabolizing enzymes (DMEs), such as glutathione S-transferase (GST) and NAD(P)H:quinone oxidoreductase 1 (NQO1), play a major role in the cellular detoxification of pharmaceutical agents and carcinogens. Previously, we reported the inhibitory effects of human liver microsomal cytochrome P450 3A4 and 2D6, phase 1 DMEs, by extracts from 78 herbal medicines. In the present study, we investigated whether phase 2 DME activity in mammalian cells was affected by the herbal extracts. Among the herbal extracts tested, GST and NQO1 activities in Clone 9 cells, a cultured cell line from normal rat liver, were increased more than 1.5-fold by treatment with Incised Notopterygium Rhizome, Magnolia Bark, Saussurea Root, and Magnolia Flower extracts. On the other hand, both of those activities were decreased to less than one-fifth by treatment with Cassia Bark and Rhubarb extracts. Pretreatment of Clone 9 cells with the former four extracts that induced phase 2 DMEs resulted in protection against the cytotoxicities of the electrophiles menadione and 1-chloro-2,4-dinitrobenzene. In contrast, GST and NQO1 activities in human lung cancer A549 cells, which are known to have a high metabolism and show resistance to anticancer drugs, was significantly decreased by treatment with the Cassia Bark extract. These results suggest that phase 2 DME activity may be modulated by herbal medicines, and the modulation of phase 2 DMEs by herbal medicines might affect the action of concomitant drugs and the detoxification of carcinogens.
