Distribution and metabolism of the natural anticarcinogen phenethyl isothiocyanate in A/J mice

Eklind, Karin I.; Morse, Mark A.; Chung, Fung‐Lung

doi:10.1093/carcin/11.11.2033

Cited by 79 publications

(52 citation statements)

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“…Reaction of the isothiocyanates with abundant thiols in blood and sequestration of the GSH conjugates by GSTs, particularly GSTs Al-l, A1-2, A2-2, in the liver and kidney should result in a relatively slow excretion of such compounds. This is seen in a detailed study of metabolism of PEITC in the mouse [28].…”

Section: Kinetic Analysismentioning

confidence: 92%

Forward and reverse catalysis and product sequestration by human glutathione S-transferases in the reaction of GSH with dietary aralkyl isothiocyanates

Meyer

Crease

Ketterer

1995

Biochemical Journal

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The reversible reaction of GSH with two dietary anticarcinogens, benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC), has been studied in the absence and presence of human glutathione S-transferases (GSTs). The spontaneous reaction at pH 7.4 and 37 degrees C yielded values for k2 of 17.9 and 6.0 M-1.s-1 for GSH conjugation of BITC and PEITC respectively (forward reaction), and k1 values of 6.9 x 10(-4) and 2.4 x 10(-4) s-1 for dissociation of the respective GSH conjugates, BITC-SG and PEITC-SG (reverse reaction). GSTs A1-1, A2-2, M1a-1a and P1-1 catalysed both the forward and reverse reactions with specific activities (mumol/min per mg at 30 microM isothiocyanate or GSH conjugate) ranging from 23.1 for the GSH conjugation of BITC by GST P1-1 to 0.03 for the dissociation of BITC-SG by GST A1-1. When present at similar concentration to substrates (12 microM), GSTs A1-1 and A2-2 but not GST M1a-1a shifted the equilibrium in favour of BITC-SG or PEITC-SG. Kinetic studies confirmed that GST A1-1 interacted selectively with the GSH conjugates in the micromolar range (Km 6.9 microM, Ki 4.3 microM), whereas GST M1a-1a interacted with BITC-SG and PEITC-SG with approx. 5-fold lower affinity. In conclusion, GSTs are true catalysts; at high intracellular concentration they also sequester GSH conjugates, promoting GSH conjugation, whereas trace extracellular GSTs promote dissociation of effluxed organic isothiocyanate-GSH conjugates.

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Section: Kinetic Analysismentioning

confidence: 92%

Forward and reverse catalysis and product sequestration by human glutathione S-transferases in the reaction of GSH with dietary aralkyl isothiocyanates

Meyer

Crease

Ketterer

1995

Biochemical Journal

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“…The synthesis of sulforaphane is outlined in Scheme 1 and the details are described below. The N-acetylcysteine conjugates of phenethyl isothiocyanate and sulforaphane were prepared using published methods (48,49). The purity of the test chemicals was verified by their proton nuclear magnetic resonance (NMR) spectra and by high-performance liquid chromatography (>98%).…”

Section: Methodsmentioning

confidence: 99%

Phenethyl Isothiocyanate and Sulforaphane and their N-Acetylcysteine Conjugates Inhibit Malignant Progression of Lung Adenomas Induced by Tobacco Carcinogens in A/J Mice

et al. 2005

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We have shown previously that naturally occurring isothiocyanates derived from cruciferous vegetables and their N-acetylcysteine conjugates inhibit lung adenoma formation induced by tobacco carcinogens in A/J mice at the postinitiation stage. The tumor-inhibitory activity by these compounds is linked with activation of activator protein and induction of apoptosis in lung tissues, suggesting that these compounds may also inhibit the development of adenomas to adenocarcinomas in lung. In this study, the chemopreventive activity of phenethyl isothiocyanate and sulforaphane and their N-acetylcysteine conjugates during progression of lung adenomas to malignant tumors was investigated in A/J mice. Mice were divided into 14 groups and treated with a mixture of 3 Mmol benzo(a)pyrene [B(a)P] and 3 Mmol 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) given by gavage once weekly for 8 weeks. Twenty weeks after the beginning of carcinogen administration, a total of 20 mice in the treatment groups were sacrificed with an average yield of 7.3 F 4.5 lung adenomas per mouse. The remaining mice in each group were fed diets containing phenethyl isothiocyanate (3 and 1.5 mmol/kg diet), sulforaphane (3 and 1.5 mmol/kg diet), phenethyl isothiocyanate-N-acetylcysteine (8 and 4 mmol/kg diet), sulforaphane-N-acetylcysteine (8 and 4 mmol/kg diet) during weeks 21 to 42. Four mice in each of the high-dose treatment groups were sacrificed during weeks 28 and 36 and the bioassay was terminated during week 42; lung tissues were harvested for histopathologic examination of tumors and for cell proliferation (proliferating cell nuclear antigen) and apoptosis (caspase-3) assays using immunohistochemical staining. At termination, the incidence of adenocarcinoma in the 3 mmol/kg diet phenethyl isothiocyanate group and 8 mmol/kg diet phenethyl isothiocyanate-N-acetylcysteine group was reduced to 19% and 13%, respectively, compared with 42% in the carcinogen-treated control group. At the lower doses, phenethyl isothiocyanate and its N-acetylcysteine conjugate also inhibited the incidences of lung adenocarcinoma, however, the decreases were not statistically significant. The lung tumor incidences in groups treated with sulforaphane-N-acetylcysteine in the diet were also significantly reduced to 11% or 16%. Furthermore, the malignant lung tumor multiplicity was significantly reduced from 1.0 tumor/ mouse in the carcinogen-treated control group to 0.3 in the sulforaphane low-dose group, 0.3 and 0.4 in the two sulforaphane-N-acetylcysteine groups, and 0.4 in the phenethyl isothiocyanate high-dose group. The malignant tumor multiplicities in other treatment groups were also reduced (0.5-0.8 tumors/mouse), but not significantly. Unlike lung adenocarcinomas, both incidences and multiplicities of lung adenomas were not much affected by treatment with isothiocyanates or their conjugates. Immunohistochemical examination of the lung tumors from all time points indicated that significant reduction in proliferating cell nuclear antigen and induction...

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“…PEITC was obtained from Aldrich (Milwaukee, WI) and its NAC conjugate was synthesized using the method described previously (38). Unless specified otherwise, A549 cells were treated with 10 or 25 Amol/L of PEITC-NAC.…”

Section: Methodsmentioning

confidence: 99%

N-Acetylcysteine Conjugate of Phenethyl Isothiocyanate Enhances Apoptosis in Growth-Stimulated Human Lung Cells

et al. 2005

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We previously showed that dietary treatment with the N-acetylcysteine conjugate of phenethyl isothiocyanate (PEITC-NAC) inhibited benzo(a)pyrene-induced lung tumorigenesis in A/J mice, and that tumor inhibition was associated with induction of activator protein-1 (AP-1) activity and stimulation of apoptosis in the lungs of mice. In the present study, we show that PEITC-NAC also induces apoptosis and AP-1 activity in human lung adenocarcinoma A549 cells, and that activation of AP-1 is important in PEITC-NAC induced apoptosis in these cells. PEITC-NAC induced AP-1 binding activity in A549 cells in a dose-and time-dependent manner; peak activity appeared at 10 Mmol/L after 24 hours. At that time, flow cytometric analysis showed a sub-G 1 peak, indicating that f4.5% of the cells had undergone apoptosis. When wild-type c-jun cDNA was transfected into A549 cells, PEITC-NAC-mediated apoptosis was greatly increased in the c-jun-transfected cells compared with the control vector-transfected cells, based on cell morphology and analysis of DNA fragmentation. Furthermore, cells that were pretreated with 100 nmol/L 12-O-tetradecanoyl phorbol-13-acetate, and then treated with 25 Mmol/L PEITC-NAC, underwent enhanced apoptosis compared with cells that were treated with PEITC-NAC alone; cells treated with 12-Otetradecanoyl phorbol-13-acetate alone showed active cell growth without apoptosis. Bivariate flow cytometric analysis of DNA strand breaks versus DNA content showed that apoptosis induced by PEITC-NAC occurred predominantly in the G 2 -M phase. These findings suggest that growth-stimulated cells with an elevated basal AP-1 activity, i.e., A549 cells transfected with wild-type c-jun or treated with a tumor promoter, were more sensitive to PEITC-NAC-mediated apoptosis. The observation that PEITC-NAC induces apoptosis predominantly in growth-promoted cells, such as neoplastic cells, suggests a selective mechanism by which PEITC-NAC inhibits lung carcinogenesis. (Cancer Res 2005; 65(18): 8538-47)

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Distribution and metabolism of the natural anticarcinogen phenethyl isothiocyanate in A/J mice

Cited by 79 publications

References 0 publications

Forward and reverse catalysis and product sequestration by human glutathione S-transferases in the reaction of GSH with dietary aralkyl isothiocyanates

Forward and reverse catalysis and product sequestration by human glutathione S-transferases in the reaction of GSH with dietary aralkyl isothiocyanates

Phenethyl Isothiocyanate and Sulforaphane and their N-Acetylcysteine Conjugates Inhibit Malignant Progression of Lung Adenomas Induced by Tobacco Carcinogens in A/J Mice

N-Acetylcysteine Conjugate of Phenethyl Isothiocyanate Enhances Apoptosis in Growth-Stimulated Human Lung Cells

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