Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadien-3,5-dione] is a potent antioxidant derived from the spice turmeric. It exerts cancer chemopreventive efficacy in a wide variety of rodent models of carcinogenesis (Kelloff et al, 1994). In common with several other diet-derived polyphenols, curcumin has low systemic bioavailability (Ireson et al, 2001). This pharmacokinetic feature of curcumin, which has been observed across several species, is the result of poor absorption and avid metabolic conjugation and reduction (Ireson et al, 2002; Sharma et al, submitted for publication). Despite the evidence that curcumin is poorly available following oral administration, there are reports that curcumin at 50–200mgkg−1 doses exerts biological activity on sites distant from the locus of absorption in rodents, such as breast (Inano and Onoda, 2002), prostate (Frank et al, 2003), lung (Menon et al, 1995) and especially the liver (Busquets et al, 2001; Park et al, 2001; Nanji et al, 2003). Studies on gall bladder contractility following oral curcumin in humans suggest that curcumin may exert biological actions at doses of 20mg (Rasyid & Lelo 1999; Rasyid et al, 2002).
Curcumin is thought to exert its chemopreventive efficacy via mechanisms including antioxidation and prevention of oxidative DNA damage. In ApcMin+ mice, a model of familial adenomatous polyposis, dietary curcumin reduced adenoma burden (Perkins et al, 2002b), which was accompanied by a reduction in adenoma levels of the oxidative DNA adduct (2-deoxy-β-dierythropentafuranosyl)pyrimido[1,2-a]-purin-10(3H)-one (malondialdehyde-DNA adduct, M1G) (Perkins et al, 2002a). Other mechanisms by which curcumin may exert chemopreventive action are interference with the transcription of the enzyme cyclooxygenase-2 (COX-2) (Plummer et al, 1999), induction of apoptosis (Kuo et al, 1996; Kawamori et al, 1999) and antiangiogenesis (Arbiser et al, 1998). The concentrations of curcumin needed to exert these effects in cells in vitro, range from 5 to 50μM (Sharma, 1976; Kunchandy and Rao, 1990; Huang et al, 1991; Tonessan and Greenhill, 1992; Reddy and Lokesh, 1992; Subramanian et al, 1994; Plummer et al, 1999). Little is known about the potential pharmacological efficacy of products of the metabolic conjugation and reduction of curcumin. Curcumin metabolites were much less capable of suppressing COX-2 transcription in cells in vitro than the parent compound (Ireson et al, 2002), indicating that chemopreventive efficacy may be in the main mediated by curcumin per se and that metabolic conjugation and reduction constitute pharmacological deactivation steps.
The disposition of curcumin in liver tissue, portal circulation and bile is unknown in humans. Therefore, we aimed to determine the levels of curcumin achievable in human liver following oral administration of curcumin. In particular, the hypothesis was tested that oral consumption of curcumin could produce liver tissue concentrations in humans consistent with levels shown to exert pharmacological action in vitro. These data could help to assess the feasibility of using curcumin as part of a strategy to prevent the development of hepatic metastases following resection of primary colorectal adenocarcinomas.