Carcinogenesis, Vol. 22, No. 3, 425-431,
March 2001
© 2001 Oxford University Press
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION |
Molecular mechanism of rapid cellular accumulation of anticarcinogenic isothiocyanates
Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA Email: yzhang{at}jhmi.edu
Isothiocyanates (ITCs) are abundant in foods derived from vegetables, and many ITCs are potent cancer chemoprotective agents in animal systems. We previously showed that many ITCs rapidly accumulated in cells to very high concentrations (up to millimolar levels), and the accumulations appeared to play a critical role in determining their activities in inducing anticarcinogenic Phase 2 enzymes. Subsequent studies showed that ITCs were principally accumulated as glutathione (GSH) conjugates in cells and that cellular GSH might be the major driving force for ITC accumulation by undergoing conjugation with the entering ITCs. To elucidate the molecular mechanism responsible for the accumulation, the dependence of cellular ITC uptake on conjugation with GSH, as well as the role of cellular GSH transferases (GSTs) known to promote the conjugation was investigated. In addition, the role of ITC lipophilicity in ITC uptake was also addressed. All experiments were conducted with four dietary ITCs: allyl-ITC, benzyl-ITC, phenethyl-ITC and sulforaphane [1-isothiocyanato-(4R,S)-(methylsulfinyl)butane]. Initial uptake rates of the four ITCs in human breast cancer cells (MCF-7) closely correlated with the non-enzymatic second-order rate constants of GSH conjugation reaction with the ITCs. Moreover, elevating cellular GSH levels also resulted in nearly proportional increases in cellular ITC uptake. In MCF-7 cells that overexpress human GST P1-1, the initial uptake rates of ITCs also increased linearly with an increase in the specific GST activity. Interestingly, lipophilicity of ITCs did not seem to influence ITC uptake by cells. Taken together, it is concluded that ITCs are taken up by cells predominantly, if not entirely, through GSH conjugation reactions in cells, and that cellular GST promotes ITC uptake by enhancing the conjugation reaction.
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