Citrus auraptene exerts dose-dependent chemopreventive activity in rat large bowel tumorigenesis: the inhibition correlates with suppression of cell proliferation and lipid peroxidation and with induction of phase II drug-metabolizing enzymes.
In our previous short-term experiment, Citrus auraptene inhibited the development of azoxymethane (AOM)-induced aberrant crypt foci, which are precursor lesions for colorectal carcinoma. In the present study, the possible inhibitory effect of dietary administration of auraptene was investigated using an animal colon carcinogenesis model with a colon carcinogen AOM. Male F344 rats were given s.c. injections of AOM (15 mg/kg body weight) once a week for 3 weeks to induce colon neoplasms. They also received diets containing 100 or 500 ppm auraptene for 4 weeks in groups of "initiation" feeding, starting 1 week before the first dosing of AOM. The diets containing auraptene were also given to rats for 38 weeks in groups of "postinitiation" feeding. At the termination of the study (38 weeks), dietary administration of auraptene caused dose-dependent inhibition in AOM-induced large bowel carcinogenesis. Auraptene feeding during the initiation phase reduced the incidence of colon adenocarcinoma by 49% at 100 ppm (P = 0.099) and 65% at 500 ppm (P = 0.0075). Auraptene administration during the postinitiation phase inhibited the incidence of colon adenocarcinoma by 58% at 100 ppm (P = 0.021) and 65% at 500 ppm (P = 0.0075). Also, the multiplicity of colon carcinoma was significantly reduced by initiation feeding at a dose level of 500 ppm (P < 0.01) and postinitiation feeding at a level of 100 and 500 ppm (P < 0.05 and P < 0.01, respectively). Feeding of auraptene suppressed the expression of cell proliferation biomarkers (ornithine decarboxylase activity and polyamine content) in the colonic mucosa and reduced the production of aldehydic lipid peroxidation [malondialdehyde and 4-hydroxy-2(E)-nonenal]. In addition, auraptene increased the activities of Phase II drug-metabolizing enzymes (glutathione S-transferase and quinone reductase) in the liver and colon. These findings suggest that the inhibitory effects of auraptene on AOM-induced colon tumorigenesis at the initiation level might be associated, in part, with increased activity of Phase II enzymes, and those at the postinitiation stage might be related to suppression of cell proliferation and lipid peroxidation in the colonic mucosa.
Tanaka
T
T
First Department of Pathology, Kanazawa Medical University, Uchinada, Ishikawa, Japan. takutt@kanazawa-med.ac.jp
Kawabata
K
K
Kakumoto
M
M
Hara
A
A
Murakami
A
A
Kuki
W
W
Takahashi
Y
Y
Yonei
H
H
Maeda
M
M
Ota
T
T
Odashima
S
S
Yamane
T
T
Koshimizu
K
K
Ohigashi
H
H
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D002957:Citrus / Q000737:chemistry; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D003374:Coumarins / Q000627:therapeutic use*; D004790:Enzyme Induction; D005982:Glutathione Transferase / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009955:Ornithine Decarboxylase / Q000378:metabolism; D011073:Polyamines / Q000097:blood / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D000447:Aldehydes; D016588:Anticarcinogenic Agents; D003374:Coumarins; D009363:Neoplasm Proteins; D011073:Polyamines; D008315:Malondialdehyde; D016660:NAD(P)H Dehydrogenase (Quinone); D005982:Glutathione Transferase; D009955:Ornithine Decarboxylase; C105832:aurapten; C027576:4-hydroxy-2-nonenal