Chemoprevention of benzo[a]pyrene‐induced forestomach cancer in mice by natural phthalides from celery seed oil

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Abstract
Bioassay‐directed fractionation of celery seed oil from the plant Apium graveolens (Umbel‐liferae) led to the isolation of five natural products, including d‐limonene, p‐mentha‐2,8‐dien‐1‐ol, p‐mentka‐8(9)‐en‐1,2‐diol, 3‐n‐butyl phthalide, and sedanolide. Of these compounds p‐mentha‐2,8‐dien‐1‐ol, 3‐n‐butyl phthalide, and sedanolide exhibited high activities to induce the detoxifying enzyme glutathione S‐transferase (GST) in the target tissues of female A/J mice. 3‐n‐Butyl phthalide and sedanolide (20 mg/dose every two days for a total of 3 doses) increased GST activity 4.5–5.9 and 3.2–5.2 times over the controls in the mouse liver and small intestinal mucosa, respectively. At the same dose, p‐mentha‐2,8‐dien‐1‐ol induced GST activity about 3.7‐fold above that of the controls. Thus, these compounds were further tested for their ability to inhibit benzo[a]pyrene‐ (BP) induced tumorigenesis in mice. After treatment with 3‐n‐butyl phthalide and sedanolide, the tumor incidence was reduced from 68% to 30% and 11%, respectively. About 67% and 83% reduction in tumor multiplicity was also observed with 3‐n‐butyl phthalide and sedanolide. p‐Mentha‐2,8‐dien‐1‐ol produced only a small or no significant reduction of forestomach tumor formation. The data indicating that 3‐n‐butyl phthalide and sedanolide were both active in tumor inhibition and GST assays suggested a correlation between the inhibitory activity and the GST‐inducing ability. The phthalides are known to determine the characteristic odor of celery. The results suggest that phthalides, as a class of bioactive natural products occurring in edible umbelliferous plants, may be effective chemopreventive agents.