Chemopreventive efficacy and pharmacokinetics of curcumin in the min/+ mouse, a model of familial adenomatous polyposis.
Curcumin, the major yellow pigment in turmeric, prevents the development of adenomas in the intestinal tract of the C57Bl/6J Min/+ mouse, a model of human familial APC. To aid the rational development of curcumin as a colorectal cancer-preventive agent, we explored the link between its chemopreventive potency in the Min/+ mouse and levels of drug and metabolites in target tissue and plasma. Mice received dietary curcumin for 15 weeks, after which adenomas were enumerated. Levels of curcumin and metabolites were determined by high-performance liquid chromatography in plasma, tissues, and feces of mice after either long-term ingestion of dietary curcumin or a single dose of [(14)C]curcumin (100 mg/kg) via the i.p. route. Whereas curcumin at 0.1% in the diet was without effect, at 0.2 and 0.5%, it reduced adenoma multiplicity by 39 and 40%, respectively, compared with untreated mice. Hematocrit values in untreated Min/+ mice were drastically reduced compared with those in wild-type C57Bl/6J mice. Dietary curcumin partially restored the suppressed hematocrit. Traces of curcumin were detected in the plasma. Its concentration in the small intestinal mucosa, between 39 and 240 nmol/g of tissue, reflects differences in dietary concentration. [(14)C]Curcumin disappeared rapidly from tissues and plasma within 2-8 h after dosing. Curcumin may be useful in the chemoprevention of human intestinal malignancies related to Apc mutations. The comparison of dose, resulting curcumin levels in the intestinal tract, and chemopreventive potency suggests tentatively that a daily dose of 1.6 g of curcumin is required for efficacy in humans. A clear advantage of curcumin over nonsteroidal anti-inflammatory drugs is its ability to decrease intestinal bleeding linked to adenoma maturation.
Perkins
Sarah
S
Cancer Biomarkers and Prevention Group, Department of Oncology, University of Leicester, Leicester, United Kingdom.
Verschoyle
Richard D
RD
Hill
Kirsti
K
Parveen
Ifat
I
Threadgill
Michael D
MD
Sharma
Ricky A
RA
Williams
Marion L
ML
Steward
William P
WP
Gescher
Andreas J
AJ
D000236:Adenoma / Q000517:prevention & control*; D011125:Adenomatous Polyposis Coli / Q000517:prevention & control* / Q000662:veterinary; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000517:prevention & control*; D003474:Curcumin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004195:Disease Models, Animal; D006471:Gastrointestinal Hemorrhage / Q000517:prevention & control; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D006400:Hematocrit; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017354:Point Mutation; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D003474:Curcumin