Mechanism of differential potencies of isothiocyanates as inducers of anticarcinogenic Phase 2 enzymes.
Isothiocyanates occur in many edible plants and are consumed in substantial quantities by humans. A number of isothiocyanates block chemical carcinogenesis in a variety of animal models by inhibiting Phase 1 enzymes involved in carcinogen activation and by inducing Phase 2 enzymes that accelerate the inactivation of carcinogens. There are large but unexplained potency differences among individual isothiocyanates. When murine hepatoma (Hepa 1c1c7) and several other cell lines were exposed to low concentrations (1-5 microM) of certain isothiocyanates, the intracellular isothiocyanate/dithiocarbamate concentrations (measured by cyclocondensation with 1,2-benzenedithiol) rose rapidly (30 min at 37 degrees C) to very high levels (e.g., 800-900 microM). The intracellular accumulation of isothiocyanates/dithiocarbamates was temperature, structure, and glutathione dependent and could not be saturated under experimentally achievable conditions. When murine hepatoma cells were exposed to nine isothiocyanates (5 microM for 24 h at 37 degrees C) that differed considerably in structure and Phase 2 enzyme inducer potencies, the intracellular concentrations (area under curve) correlated closely and linearly with their potencies as inducers of the Phase 2 enzymes: NAD(P)H:quinone reductase and glutathione S-transferases. Isothiocyanates that did not accumulate to high levels were not inducers. These observations suggest strongly that induction of Phase 2 enzymes depends on intracellular levels of isothiocyanates/dithiocarbamates. Depletion of glutathione by treatment of Hepa cells with buthionine sulfoximine increased the inducer potencies of several isothiocyanates but could not be directly related to changes in intracellular isothiocyanate/dithiocarbamate concentrations, suggesting that glutathione may play several roles in the induction process.
Zhang
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Y
Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Talalay
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P
D000818:Animals; D016588:Anticarcinogenic Agents / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000096:biosynthesis; D005978:Glutathione / Q000032:analysis / Q000502:physiology; D005982:Glutathione Transferase / Q000096:biosynthesis*; D017879:Isothiocyanates / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
D016588:Anticarcinogenic Agents; D017879:Isothiocyanates; D016660:NAD(P)H Dehydrogenase (Quinone); D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D005978:Glutathione