Chemoprevention of benzo[a]pyrene-induced forestomach cancer in mice by natural phthalides from celery seed oil.
Bioassay-directed fractionation of celery seed oil from the plant Apium graveolens (Umbelliferae) led to the isolation of five natural products, including d-limonene, p-mentha-2,8-dien-1-ol, p-mentha-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.
Zheng
G Q
GQ
LKT Laboratories, Minneapolis, MN 55413.
Kenney
P M
PM
Zhang
J
J
Lam
L K
LK
D000818:Animals; D001564:Benzo(a)pyrene; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005982:Glutathione Transferase / Q000187:drug effects / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D010795:Phthalic Acids / Q000302:isolation & purification / Q000627:therapeutic use*; D010938:Plant Oils / Q000627:therapeutic use*; D013270:Stomach / Q000187:drug effects / Q000201:enzymology*; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000517:prevention & control*
D010795:Phthalic Acids; D010938:Plant Oils; D001564:Benzo(a)pyrene; D005982:Glutathione Transferase