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Pre-clinical pharmacology and cancer chemopreventive activity of indole-3-carbinol and 3,3'-diindolylmethane
thesisposted on 2014-12-15, 10:30 authored by Mark John. Anderton
Indole-3-carbinol (I3C), a dietary constituent derived from cruciferous vegetables has been shown to exert anti-tumour and chemopreventive activity in vitro and in vivo. 3,3'-diindolylmethane (DIM), an acid condensation product of I3C, exerts promising activity and is thought to be partially responsible for the chemopreventive activity of orally administered I3C. In order to aid the development of I3C or DIM as cancer chemopreventive agents, the pre-clinical pharmacology and cancer chemopreventive activities were explored. An HPLC method was developed and validated to enable accurate pharmacokinetic studies of both compounds. The tissue distribution and pharmacokinetics of I3C, DIM and an absorption-enhanced DIM formulation [(BioResponse-DIMÃ¢; BR-DIM)] were investigated. I3C was rapidly absorbed, distributed and eliminated, with peak levels in plasma and tissues occurring within the first 15 min and falling below the limit of detection by 1 h. Acid condensation products and oxidative metabolites were identified in mice that received I3C. Following administration of crystalline DIM or BR-DIM, absorption was rapid with maximal plasma and tissue concentrations occurring within 0.5-1 h. In contrast to I3C, DIM could be quantified in the plasma and most tissues at all time points up to and including 24 h. A physiologically based pharmacokinetic model was developed to characterise the pharmacokinetics of BR-DIM and crystalline DIM. BR-DIM exhibited approximately 50% higher bioavailability than the crystalline form. In vitro, DIM was more potent at inhibiting the growth of the MDA MB468 breast cell line than the normal derived HBL100 line. DIM induced apoptosis and inhibited phosphorylation of protein kinase B in MDA MB468 cells with higher potency than I3C. Neither I3C nor DIM, whether administered in the diet or by repeated oral gavage, was able to inhibit the growth of MDA MB468 xenografts in nude mice. In conclusion, these results further our understanding of the in vivo pharmacology and cancer chemopreventive activity of I3C and DIM.
Date of award2004-01-01
Awarding institutionUniversity of Leicester