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Division of Carcinogenesis and Molecular Epidemiology, American Health Foundation, Valhalla, New York 10595 [Y-M. Y., C. C. C., W. D., S. A., F-L. C.], and Pathology and Toxicology [C-X. W., J. W.], Research Animal Facility [J. R.], Department of Medicine, New York Medical College, Valhalla, New York 10595 [J. W. C.]
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ABSTRACT |
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B activities were evaluated by gel shift assay. The AP-1 binding activity was remarkably increased in lung tissue from both the BITC-NAC and PEITC-NAC groups. No change in nuclear factor-B binding activity was found, however. Phosphorylation of p53 was also higher than the constitutive levels in both ITC-NAC-treated groups, but no induction of p53 expression was detected. This study demonstrates the chemopreventive efficacy of the NAC conjugates of PEITC and BITC administered in the diet after a single dose of B(a)P for lung tumorigenesis and provides the first in vivo evidence that activation of MAP kinases, AP-1 transcription factors, p53 phosphorylation, and the induction of apoptosis may be involved in the chemopreventive activity of these compounds. |
Introduction |
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In addition to the activities of ITCs on phase I and phase II enzymes, recent studies in cell culture have shown that ITCs and their conjugates induce apoptosis (14, 15, 16, 17, 18) , a protective mechanism against neoplastic development in which genetically damaged or improperly divided cells are eliminated. In vitro and in vivo studies have demonstrated that suppression of apoptosis is involved in tumor promotion caused by chemical agents. It has been reported that ITCs induce JNK activation in cultured cells, and that this activation is associated with induction of apoptosis. Other studies have demonstrated that PEITC induces p53 transactivation in a dose- and time-dependent manner in a mouse epidermal cell line with accompanying apoptosis. In contrast, PEITC did not induce apoptosis in p53 (-/-) mouse embryo fibroblasts, suggesting that a p53-mediated mechanism is involved in ITC-induced apoptosis (14) . Results of these in vitro studies suggest that ITCs may exhibit chemopreventive potential when administered during the postinitiation phase of tumorigenesis. Indeed, a recent study showed that the NAC conjugates of ITCs given p.o. after the administration of azoxymethane inhibit aberrant crypt foci formation in the colon of F344 rats (19) .
In this study, the chemopreventive potential of the NAC conjugates of two widely occurring ITCs, BITC and PEITC, administered in the diet during the postinitiation phase of B(a)P-induced lung tumorigenesis in A/J mice, was investigated. The molecular mechanisms involving apoptosis and changes in related genes, including MAP kinases, AP-1, and p53, were examined using the mouse lung tissues obtained during the tumor bioassay. This study is part of our long-range goal to discover mechanism-based chemopreventive agents for ex-smokers who remain at an increased risk of lung cancer even after smoking cessation.
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Materials and Methods |
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The ITC conjugates were incorporated (15 µmol/g diet) into AIN-76A diets (5% corn oil) by mixing with dextrose prior to diet preparation. The conjugates, 9.36 g of BITC-NAC (15 mmol) or 9.79 g of PEITC-NAC (15 mmol), were dissolved in 50 ml of ethyl acetate and then mixed with 200 g of dextrose to ensure even coating of dextrose particles. After mixing with dextrose, the solvent was removed using a rotary evaporator and further dried using a vacuum pump (2–3 h). Diets were prepared in 1–2-kg batches and were stored at 4°C in a container purged with nitrogen. PEITC-NAC and BITC-NAC were stable for at least 1 month. Stability was determined by extraction of 0.5-g portions of the diet with 2.5 ml of methanol (2x). The methanol extracts were combined, and a 1-ml aliquot was filtered using a 0.47-µm syringe filter. A 10-µl sample was then analyzed on high-performance liquid chromatography (12) .
Tumor Bioassay.
Female strain A mice (Jackson Laboratories, Bar Harbor, ME) of 4 weeks of age were housed under quarantine in polycarbonate cages (5 mice/cage) and provided modified AIN 76A diet (5% corn oil) and acidified drinking water ad libitum. The mice were maintained on a 12-h light:12-h dark regimen at 22 ± 5°C and 50 ± 20% relative humidity. After 1 week, the mice were weighed and distributed into four groups containing 30–35 mice on the basis of body weight. At 7 weeks of age, the mice in groups 1–3 were gavaged with a single dose of 20 µmol of B(a)P in 0.2 ml of cottonseed oil; group 4 received the vehicle only. Two days after dosing with the carcinogen, diets containing BITC-NAC (15 µmol/g, group 2) and PEITC-NAC (15 µmol/g, group 3) were provided. Groups 1 [B(a)P control] and 4 (vehicle only) remained on the modified AIN-76A diet with 5% corn oil. Tap water was provided ad libitum during the course of the bioassay. Mice were observed daily; diets were replenished on the fourth day of the week and completely replaced on the seventh day. Mice were weighed weekly for 4 weeks and then monthly and at termination. At 84 days after B(a)P dosing, 4 mice/group were killed (CO2, cervical dislocation) to harvest lung tissues for molecular and immunohistochemical studies and to quantify lung adenomas, if present. At 140 days after B(a)P, the remaining mice in each group were killed. The number of lung tumors was recorded, and lobes of lungs were placed in 10% phosphate-buffered formalin for histological and immunohistochemical analysis. The remainder of the lung lobes was snap frozen in liquid nitrogen.
In the second bioassay, A/J mice of the same age from The Jackson Laboratory were treated using an identical protocol and maintained under the same conditions as described above for 21 days only. Diet consumption was measured twice weekly, and body weights were determined weekly until termination. Mice were sacrificed at termination for harvesting lung tissues to be used in molecular studies. Mean tumor multiplicity and body weights at each time point were compared between groups using Student’s t test.
ISEL.
Formalin-fixed, paraffin-embedded sections from the lungs of mice of the four experimental groups were prepared. ISEL (or terminal deoxynucleotide transferase dUTP nick end-labeling) was performed using an apoptosis detection kit (Enzo Diagnostics, Farmingdale, NY) according to the manufacturer’s instructions with the following exceptions: (a) endogenous peroxidase was blocked using 3% hydrogen peroxide in methanol for 15 min; (b) labeling solution was made up of 45 µl of label reagent, 0.3 µl (10 µ/µl) of terminal deoxynucleotide transferase and 4.7 µl of sterile, distilled water. Sections were incubated in a 37°C water bath for 15 min; (c) the color reaction with 3,3'-diaminobenzidine was completed in 10 min on a 37°C heating block; and (d) counterstaining was done with Gill’s 2 hematoxylin (Shandon-Lipshaw, Pittsburgh, PA) at a 1:10 dilution for 30 s. Sections of liver were used as controls. Cells undergoing apoptosis identified by ISEL were counted under a microscope; a total of 1500 cells of alveolar epithelium from 20 to 24 visual fields/slide were tallied. Three slides/treatment group were analyzed.
Western Blot Analysis.
Western blot analysis was performed as described previously (20)
. Briefly, total proteins were prepared from each group of pooled mouse lungs. Lung samples were removed and immediately placed in 1x PBS with 2 mM DTT, 0.1 mM EDTA, and a protease inhibitor mixture. The samples were then immediately transferred and homogenized in a radioimmunoprecipitation assay buffer with the protease inhibitors, aprotinin (1 µg/ml), leupeptin (1 µg/ml), pepstatin (1 µM), phenylmethylsulfonyl fluoride (0.1 mM), and the phosphatase inhibitors Na3VO4 (1 mM) and NaF (1 mM). Samples were centrifuged at 16,500 x g for 30 min at 4°C. The supernatants were collected as the total proteins. Equal amounts (30 µg) of the total proteins were boiled for 5 min in the presence of Laemmli sample buffer, loaded on each lane, and separated by 10% SDS-PAGE. The gels were then transferred to nitrocellulose membranes. Equal amounts of protein loading for each lane was checked by Ponceau (Sigma Chemical Co., St. Louis, MO) staining. The anti-JNK1, anti-phospho-JNK1/2, anti-Bax (Santa Cruz Biotechnology, Santa Cruz, CA), anti-p53, anti-p21WAF1/CIP1 (Oncogene Research Products, Cambridge, MA), anti-phospho-p38, anti-phospho-Erk1/2, and anti-phosphor-p53: Ser-6, Ser-9, Ser-15, Ser-20, and Ser-392 (Cell Signaling, Beverly, MA) antibodies were diluted to the concentration according to commercial recommendations. Immunoreactive bands were detected with an enhanced chemiluminescence kit (ECL; Amersham Pharmacia Biotech, Piscataway, NJ).
EMSA.
Double-stranded oligonucleotides containing the consensus binding site for AP-1, mutated AP-1, NF-B, and mutated NF-B were purchased commercially (Santa Cruz Biotechnology, Santa Cruz, CA). EMSA was performed as described previously (21)
. Briefly, all oligonucleotides were labeled with [
-32P]ATP (6000 Ci/mmol; Amersham Pharmacia Biotech) using polynucleotide kinase (Promega Corp., Madison, WI) according to standard procedures. The labeled DNA (0.4 ng, 4400 cpm) was incubated with 10 µg of total proteins for 10 min at room temperature in the presence of 1 µg of poly(deoxyinosinic-deoxycytidylic acid) oligomer (Boehringer Mannheim, Indianapolis, IN) and DNA-binding buffer. The complexes were then separated on a 7.5% polyacrylamide gel and autoradiographed.
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Results |
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. Animals were observed throughout the bioassay and showed no signs of toxicity. However, mice fed the diet containing ITC compounds gained less body weight than control mice. At termination, the average body weight of groups 2 (22.9 g) and 3 (22.8 g) showed approximately 10–12% less weight compared with groups 1 (25.8 g) and 4 (25.7 g). The food consumption records showed that during the bioassay, all mice gained 
0.1 g of weight/gram of food consumed. The reduction in body weight gains in these groups were, therefore, consistent with the reduced food consumption of mice in groups 2 and 3 compared with groups 1 and 4. These results suggest that the reduction in body weight gains for mice in the ITC-treated groups was mainly attributable to palatability.
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2-fold in the BITC-NAC- and PEITC-NAC-treated groups at 84 days (Fig. 1)
, just before the tumors appeared. Similar results were obtained from BITC-NAC and PEITC-NAC groups after 140 days, when tumors had developed. Nontumorous lung tissue of these two groups had a >2-fold increase in apoptosis (2.4-fold for BITC-NAC and 2.3-fold for PEITC-NAC). Because alveolar epithelial cells are mostly quiescent, a 2-fold increase of the apoptotic cells may critically result in reduction of tumor multiplicity.
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, the phosphorylation levels on Ser-185 and Ser-188 of JNK1 and JNK2, detected by the phospho-specific antibody, were increased in lung tissue of ITC-NAC-treated mice obtained 21 days after B(a)P administration. B(a)P (Fig. 2A
, Lane 2) -treated groups showed no significant change in JNK1 and JNK2 phosphorylation levels from the untreated group (Fig. 2A
, Lane 5). Groups treated with B(a)P plus BITC-NAC and PEITC-NAC (Fig. 2A
, Lanes 3 and 4) showed an increase of JNK1 (p46) phosphorylation levels, whereas JNK2 (p54) phosphorylations were only slightly induced, compared with JNK1. The total proteins isolated from NIH 3T3 cells 15 min after UV (20 J) treatment served as a positive control for phospho-JNK1 and JNK2 (Fig. 2A
, Lane 1). Fig. 2B
shows that equal amounts of JNK1 were expressed in all groups. The results indicate that ITCs induce JNK1 phosphorylation but not its expression. When the total proteins in mouse lung tissue obtained 140 days after B(a)P treatment were examined, similar results were obtained showing an approximately 2–3-fold increase of phosphorylation of JNK1 and JNK2 by ITC-NAC conjugate treatment (data not shown).
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indicates that p38 phosphorylation levels did not change in mice treated with B(a)P (group 1, Lane 2) compared with the untreated mice in group 4 (Lane 5). However, the ITC-NAC-treated groups 2 and 3 showed a significant increase in p38 phosphorylation. The UV-treated NIH 3T3 cells as a positive control showed a strong phospho-p38 band. Erk1 and Erk2 activities were detected in the same blot (Fig. 2D)
. The mice treated with B(a)P fed the control diet had a low level of phospho-Erk2 (p42), whereas the groups fed the diets containing ITC conjugates showed an elevated phosphorylation level of Erk2. However, Erk1 phosphorylations were barely detectable in all groups.
Activation of p53 Phosphorylation.
To investigate the possible role of p53 in apoptosis induced by BITC-NAC or PEITC-NAC, we analyzed the expression of p53 and its phosphorylation level in lungs obtained at termination of the bioassay by Western blot using specific antibodies. Although treatment with ITC compounds did not cause apparent accumulation of p53 or change the level of p53 expression (Fig. 3A
, lower panel), the level of phosphorylation of p53 at Ser-15 appeared to be enhanced (Fig. 3A
, upper panel). BITC-NAC caused only a moderate increase, whereas the PEITC-NAC treatment resulted in a stronger increase in the phosphorylation. The phosphorylation levels of p53 Ser-6, Ser-9, Ser-20, and Ser-392 were also assayed, and the results are summarized in Fig. 3B
. Phosphorylation at Ser-9, Ser-20, and Ser-392 was induced in the ITC-NAC-treated groups when compared with the B(a)P-treated (group 1) and untreated groups (group 4). The phosphorylation at Ser-6 remained unchanged.
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shows that p21WAF1/CIP1 expression in the ITC-NAC-treated groups was significantly higher than that in groups 1 and 4. Although the induction of Bax expression was not as strong as p21WAF1/CIP1, it is still clear that the treated groups showed increased expression of Bax (Fig. 3D)
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Activation of Transcription Factors AP-1 but not NFB.
The increase of AP-1 and NFB binding activity has been demonstrated in cultured human colon cancer cells treated with BITC, and BITC is believed to be involved in the induction of phase II enzymes (24)
. To determine whether dietary ITC-NAC compounds affect the transcription of genes regulated by AP-1 and NFB, total protein extracts were prepared from the lung tissue of mice from all four groups 21 days after B(a)P administration. The binding activity of these proteins to AP-1 and NFB was determined using the EMSA. AP-1 binding activities were strongly induced by ITC-NAC treatments (Fig. 4A-I)
. However, NFB binding activities in ITC-NAC-treated groups were not significantly different from the control (Fig. 4B-I)
. The binding activity induced by PEITC-NAC is specific for the AP-1 sequence, because the addition of a 10x unlabeled AP-1 sequence completely abolished binding activity (Fig. 4A-II)
. Similarly, the sustained NFB binding activity is specific for the NFB target sequence because a 10x unlabeled NFB sequence effectively competed with the binding activity of the proteins from the untreated control group (Fig. 4B-II)
. Furthermore, a 10x unlabeled mutant AP-1 or NFB sequence and a 10x extra nonspecific DNA sequence did not alter the binding activity of AP-1 or NFB.
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Discussion |
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In the tumor bioassay, body weight disparities between the groups fed diets containing ITC compounds and the control groups were noted. These differences were probably caused by the reduction of food consumption in the treated groups attributable to palatability, as indicated by the food consumption data. It raises questions as to whether the inhibition of lung tumorigenesis is a result of lowered caloric intake. Several lines of evidence suggest that this is not the case: (a) Little is known on the relationship of caloric restriction and lung tumorigenesis, but the extent of the decreases in body weight gain is probably too small to cause such a sizable reduction in tumor multiplicity based on published data for some other organ sites (26) . (b) Although it is known that caloric restriction could influence gene expression (27) , the molecular responses characterized in this study seem to be opposite to those found in animals on the calorie-restricted diet. For example, our studies showed that JNK1, p38, and Erk1 phosphorylation levels were induced by ITC compounds after 21 days of treatment, and AP-1 activity was also strongly induced. Liu et al. (28) reported that the calorie restriction inhibits TPA-induced AP-1 binding activity and also inhibits TPA-induced Erk activity but not p38 and JNK in the epidermis of SENCAR mice. Furthermore, our results demonstrated an induction of p53, p21, or Bax genes, yet others have shown that p53 phosphorylation and p27, p21, and p16 expression are not affected by calorie restriction in F344 rats (29) .
Numerous studies in cell culture have shown that ITCs induce MAP kinase activity, AP-1, NFB activity, and p53 activity (14, 15, 16, 17
, 24)
. Our study is the first to demonstrate that oral administration of ITC compounds at the doses that inhibit lung tumorigenesis induces MAP kinase phosphorylation, AP-1 binding activity, and p53 activity in the target tissue of tumor inhibition. Compared with the results obtained from studies in cell culture, the activation of JNK activity in mouse lung was less pronounced, yet the induction of the AP-1 activity was comparable. We did not detect any changes in NFB binding activities in the mouse lung after treatments. The differences in molecular responses between in vitro and in vivo may be attributable to factors such as the concentrations of ITCs in culture medium versus tissue-, cell-specific responses to ITCs, and/or uptake and metabolism in vivo. The activation of p53 is known to play a key role in the protection against tumorigenesis. Consistent with this, we have shown that BITC-NAC and PEITC-NAC activated p53 activity in mouse lungs by inducing phosphorylation and, subsequently, induced the expression of its effector genes, Bax and p21WAF/CIP1. However, questions regarding how these ITC compounds activate p53 phosphorylation still remain to be investigated. Taken together, we have shown that dietary ITC conjugates induce molecular responses in mouse lung similar to those seen in ITC-treated cells in vitro, supporting the contention that the effects we see in the lung are caused by ITCs released by deconjugation.
The cellular and molecular responses in mouse lungs after treatment with BITC-NAC and PEITC-NAC are known to be associated with oxidative stress. Although these compounds have not been shown specifically to cause oxidative DNA damage, some ITCs are cytotoxic, weakly mutagenic, and can stimulate lipid peroxidation in cultured cells (30
, 31)
. It is possible that ITC conjugates via deconjugation may cause oxidative DNA damage by depleting GSH and/or an alteration of the redox potential in lung cells by NAC (32
, 33)
. To respond to the changes in oxidative status, lung cells may go into apoptosis through activation of MAP kinases and p53. A proposed molecular mechanism for the inhibition of lung tumorigenesis by ITC conjugates via apoptosis is shown in Fig. 5
. Clearly, more studies are needed to substantiate this mechanism. Regardless of the biochemical nature of the cellular stress caused by them, these ITC compounds are apparently not sufficient to induce tumorigenesis, because all of our previous bioassays in A/J mice or F344 rats showed that ITCs administered alone did not cause any tumors (11
, 34) . The results of this study show that administration of ITC conjugates in the diet during the postinitiation stages of B(a)P-induced lung tumorigenesis can elicit a series of stress-related molecular responses leading to cell death that ultimately is manifested in the reduction of lung tumor formation.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by NCI Grant CA46535. This is paper no. 34 in the series "Dietary Inhibitors of Chemical Carcinogenesis." 
2 To whom requests for reprints should be addressed, at Division of Carcinogenesis and Molecular Epidemiology, American Health Foundation, Valhalla, NY 10595. Phone: (914) 789-7161; Fax: (914) 592-6317; E-mail: chungahf{at}aol.com
3 The abbreviations used are: ITC, isothiocyanate; BITC, benzyl ITC; PEITC, phenethyl ITC; NAC, N-acetylcysteine; B(a)P, benzo(a)pyrene; JNK, c-Jun NH2-terminal kinase; ISEL, in situ end-labeling; EMSA, electrophoretic mobility shift assay; NFB, nuclear factor-B; MAP, mitogen-activated protein; Erk, extracellular signal-regulated kinase; AP-1, activator protein-1.
Received 9/13/01. Accepted 11/14/01.
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-chemokine, stromal cell-derived factor-l, binds to the transmembrane G-protein-coupled CXCR-4 receptor and activates multiple signal transduction pathway. J. Biol. Chem., 273: 23169-23175, 1998.B. Biochem. Biophys. Res. Commun., 257: 149-155, 1999.[Medline]
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 K. Akagi, M. Sano, K. Ogawa, M. Hirose, H. Goshima, and T. Shirai Involvement of Toxicity as an Early Event in Urinary Bladder Carcinogenesis Induced by Phenethyl Isothiocyanate, Benzyl Isothiocyanate, and Analogues in F344 Rats Toxicol Pathol, June 1, 2003; 31(4): 388 - 396. [Abstract] [PDF]
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D. Xiao, S. K. Srivastava, K. L. Lew, Y. Zeng, P. Hershberger, C. S. Johnson, D. L. Trump, and S. V. Singh Allyl isothiocyanate, a constituent of cruciferous vegetables, inhibits proliferation of human prostate cancer cells by causing G2/M arrest and inducing apoptosis Carcinogenesis, May 1, 2003; 24(5): 891 - 897. [Abstract] [Full Text] [PDF]
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S. Sugiura, K. Ogawa, M. Hirose, F. Takeshita, M. Asamoto, and T. Shirai Reversibility of proliferative lesions and induction of non-papillary tumors in rat urinary bladder treated with phenylethyl isothiocyanate Carcinogenesis, March 1, 2003; 24(3): 547 - 553. [Abstract] [Full Text] [PDF]
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F. Kassie, M. Uhl, S. Rabot, B. Grasl-Kraupp, R. Verkerk, M. Kundi, M. Chabicovsky, R. Schulte-Hermann, and S. Knasmuller Chemoprevention of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-induced colonic and hepatic preneoplastic lesions in the F344 rat by cruciferous vegetables administered simultaneously with the carcinogen Carcinogenesis, February 1, 2003; 24(2): 255 - 261. [Abstract] [Full Text] [PDF]
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S. S. Hecht, P. Upadhyaya, M. Wang, R. L. Bliss, E. J. McIntee, and P. M.J. Kenney Inhibition of lung tumorigenesis in A/J mice by N-acetyl-S-(N-2-phenethylthiocarbamoyl)-L-cysteine and myo-inositol, individually and in combination Carcinogenesis, September 1, 2002; 23(9): 1455 - 1461. [Abstract] [Full Text] [PDF]
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D. Xiao and S. V. Singh Phenethyl Isothiocyanate-induced Apoptosis in p53-deficient PC-3 Human Prostate Cancer Cell Line Is Mediated by Extracellular Signal-regulated Kinases Cancer Res., July 1, 2002; 62(13): 3615 - 3619. [Abstract] [Full Text] [PDF]
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C. Krul, C. Humblot, C. Philippe, M. Vermeulen, M. van Nuenen, R. Havenaar, and S. Rabot Metabolism of sinigrin (2-propenyl glucosinolate) by the human colonic microflora in a dynamic in vitro large-intestinal model Carcinogenesis, June 1, 2002; 23(6): 1009 - 1016. [Abstract] [Full Text] [PDF]
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, 84 days; 
, 140 days.
, B(a)P; 
, B(a)P + BITC-NAC; 
;, untreated. Western blot analysis was performed with anti-p21WAF1/CIP1 (C) and anti-Bax (D) antibodies using total proteins of lungs. NS, a nonspecific band. UV-treated 3T3 cells in D serve as a positive control.
