Effects of dietary curcumin on glutathione S-transferase and malondialdehyde-DNA adducts in rat liver and colon mucosa: relationship with drug levels.
Curcumin prevents colon cancer in rodent models. It inhibits lipid peroxidation and cyclooxygenase-2 (COX-2) expression and induces glutathione S-transferase (GST) enzymes. We tested the hypothesis that 14 days of dietary curcumin (2%) affects biomarkers relevant to cancer chemoprevention in the rat. Levels of inducible COX-2, as reflected by prostaglandin E(2) production by blood leukocytes, were measured ex vivo. Total GST activity and adducts of malondialdehyde with DNA (M(1)G), which reflect endogenous lipid peroxidation, were measured in colon mucosa, liver, and blood leukocytes. Curcumin and its metabolites were analyzed by high-performance liquid chromatography in plasma, and its pharmacokinetics were compared following a diet containing 2% curcumin versus intragastric (i.g.) administration of curcumin suspended in an amphiphilic solvent. The curcumin diet did not alter any of the markers in the blood but increased hepatic GST by 16% and decreased colon M(1)G levels by 36% when compared with controls. Administration of carbon tetrachloride during the treatment period increased colon M(1)G levels, and this increase was prevented by dietary curcumin. Dietary curcumin yielded low drug levels in the plasma, between 0 and 12 nM, whereas tissue concentrations of curcumin in liver and colon mucosa were 0.1--0.9 nmol/g and 0.2--1.8 micromol/g, respectively. In comparison with dietary administration, suspended curcumin given i.g. resulted in more curcumin in the plasma but much less in the colon mucosa. The results show that curcumin mixed with the diet achieves drug levels in the colon and liver sufficient to explain the pharmacological activities observed and suggest that this mode of administration may be preferable for the chemoprevention of colon cancer.
Sharma
R A
RA
Department of Oncology, University of Leicester, Leicester LE1 9HN, United Kingdom.ras20@le.ac.uk
Ireson
C R
CR
Verschoyle
R D
RD
Hill
K A
KA
Williams
M L
ML
Leuratti
C
C
Manson
M M
MM
Marnett
L J
LJ
Steward
W P
WP
Gescher
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000517:prevention & control; D003474:Curcumin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018736:DNA Adducts / Q000187:drug effects / Q000378:metabolism*; D004032:Diet; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism*; D005982:Glutathione Transferase / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008315:Malondialdehyde / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D000970:Antineoplastic Agents; D018736:DNA Adducts; D008315:Malondialdehyde; D005982:Glutathione Transferase; D003474:Curcumin