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Funglung Chung - One of the best experts on this subject based on the ideXlab platform.
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Isothiocyanates suppress the invasion and metastasis of tumors by targeting fak mmp 9 activity
2017Co-Authors: Yunjeong Jeong, Funglung Chung, Hyunji Cho, Xiantao Wang, Hyangsook Hoe, Kwankyu Park, Cheorlho Kim, Hyeunwook Chang, Sangrae LeeAbstract:Isothiocyanates, which are present as glucosinolate precursors in cruciferous vegetables, have strong activity against various cancers. Here, we compared the anti-metastatic effects of Isothiocyanates (benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC), and sulforaphane (SFN)) by examining how they regulate MMP-9 expression. Isothiocyanates, particularly PEITC, suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MMP-9 activity and invasion in various cancer cell lines. By contrast, N-methyl phenethylamine, a PEITC analog without an isothiocyanate functional group, had no effect. A reporter gene assay demonstrated that BITC, PEITC, and SFN suppressed TAP-induced MMP-9 expression by inhibiting AP-1 and NF-κB in U20S osteosarcoma cells. All three compounds reduced phosphorylation of FAK, ERK1/2, and Akt. In addition, MMP-9 expression was downregulated by inhibiting FAK, ERK1/2, and Akt. Isothiocyanates-mediated inhibition of FAK phosphorylation suppressed phosphorylation of ERK1/2 and Akt in U2OS and A549 cells, along with the translocation of p65 and c-Fos, suggesting that Isothiocyanates inhibit MMP-9 expression and cell invasion by blocking phosphorylation of FAK. Furthermore, Isothiocyanates, abolished MMP-9 expression and tumor metastasis in vivo with the following efficacy: PEITC>BITC>SFN. Thus, Isothiocyanates act as anti-metastatic compounds that suppress MMP-9 activity/expression by inhibiting NF-κB and AP-1 via suppression of the FAK/ERK and FAK/Akt signaling pathways.
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phenethyl isothiocyanate and sulforaphane and their n acetylcysteine conjugates inhibit malignant progression of lung adenomas induced by tobacco carcinogens in a j mice
2005Co-Authors: Clifford C Conaway, Chung Xiou Wang, Brian Pittman, Yang Ming Yang, Joel E Schwartz, Defa Tian, Edward J Mcintee, Stephen S Hecht, Funglung ChungAbstract: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 post-initiation 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 micromol benzo(a)pyrene [B(a)P] and 3 micromol 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 +/- 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 of apoptosis (terminal nucleotidyl transferase-mediated nick end labeling and caspase-3) were observed in the isothiocyanate and isothiocyanate-N-acetylcysteine-treated groups that showed inhibition of the development of lung adenocarcinomas. The results of the study provide a basis for future evaluation of the potential of phenethyl isothiocyanate and sulforaphane and their conjugates as chemopreventive agents in smokers and ex-smokers with early lung lesions.
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Isothiocyanates glutathione s transferase m1 and t1 polymorphisms and lung cancer risk a prospective study of men in shanghai china
2000Co-Authors: Funglung Chung, Ronald K. Ross, Gerhard A. Coetzee, Stephanie J London, Jianmin Yuan, Mimi C. YuAbstract:Summary Background Dietary Isothiocyanates inhibit lung carcinogenesis in laboratory animals but human data are limited. Glutathione S-transferases M1 and T1 ( GSTM1 and GSTT1 ) conjugate Isothiocyanates leading to more rapid elimination. Common deletion polymorphisms of GSTM1 and GSTT1 abolish enzyme activity. We hypothesised that chemopreventive effects of Isothiocyanates might be heightened when enzymes that enhance their elimination are lacking. Methods We examined the relation between total isothiocyanate concentrations in urine, collected before diagnosis, and the subsequent risk of lung cancer among 232 incident cases of lung cancer and 710 matched controls from a cohort of 18 244 men in Shanghai, China, followed from 1986 to 1997. Homozygous deletion of the GSTM1 and GSTT1 genes were determined by PCR. Findings Individuals with detectable Isothiocyanates in the urine were at decreased risk of lung cancer (smoking-adjusted relative risk for lung cancer=0·65 [95% Cl 0·43–0·97]). This protective effect of Isothiocyanates was seen primarily among individuals with homozygous deletion of GSTM1 (0·36 [0·20–0·63]) and particularly with deletion of both GSTM1 and GSTT1 (0·28 [0·13–0·57]). Interpretation Isothiocyanates appeared to reduce lung-cancer risk in this cohort of Chinese men. Reduction in risk was strongest among persons genetically deficient in enzymes that rapidly eliminate these chemopreventive compounds.
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inhibition of rat liver cytochrome p450 isozymes by Isothiocyanates and their conjugates a structure activity relationship study
1996Co-Authors: Clifford C Conaway, Ding Jiao, Funglung ChungAbstract:A series of arylalkyl and alkyl Isothiocyanates, and their glutathione, cysteine, and N-acetylcysteine conjugates were used to study their inhibitory activity toward the dealkylation of ethoxyresorufin (EROD), pentoxyresorufin (PROD), and methoxyresorufin (MROD) in liver microsomes obtained from the 3-methylcholanthrene or phenobarbital-treated rats. These reactions are predominantly mediated by cytochrome P450 (P450) isozymes 1A1 and 1A2, 2B1 and 1A2, respectively. All Isothiocyanates inhibited PROD more readily than EROD. Increases in the alkyl chain length of arylalkyl Isothiocyanates to C6 resulted in an increased inhibitory potency in these assays; at longer alkyl chain lengths (C8-C10) the inhibitory potency declined. The IC50s for phenethyl isothiocyanate (PEITC) were 47, 46 and 1.8 microM for EROD, MROD and PROD, respectively. Substitution of an additional phenyl group on PEITC also increased the inhibitory potency; the IC50s for 1,2-diphenylethyl isothiocyanate (1,2-DPEITC) and 2,2-diphenylethyl isothiocyanate (2,2-DPEITC) were 0.9 and 0.26 microM for EROD, and 0.045 and 0.13 microM for PROD, respectively. The relative inhibitory potency of PEITC and its conjugates was N-acetylcysteine-PEITC (PEITC-NAC) < glutathione-PEITC (PEITC-GSH) < cysteine-PEITC (PEITC-CYS) < PEITC. The observations that the parent Isothiocyanates were more potent inhibitors than the conjugates suggest that dissociation of the conjugate is required for activity. Naturally occurring alkyl Isothiocyanates, sulforaphane (SFO) and allyl isothiocyanate (AITC), were very weak inhibitors in the assays. These results suggest the potential of Isothiocyanates as structural probes for studying P450 isozymes. In addition, the inhibitory activity of Isothiocyanates for PROD correlated with the previously demonstrated tumor inhibitory potency in (4-methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induced A/J mouse lung tumor bioassays, which supports earlier findings that P450 2B1 is one of the major isozymes involved in NNK activation and that inhibition of this isozyme is an important mechanism for the chemopreventive activity of Isothiocyanates.
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inhibition of n nitrosodimethylamine demethylase in rat and human liver microsomes by Isothiocyanates and their glutathione l cysteine and n acetyl l cysteine conjugates
1996Co-Authors: Ding Jiao, Clifford C Conaway, Mongheng Wang, Chung S Yang, Werner Koehl, Funglung ChungAbstract:Natural and synthetic Isothiocyanates and their conjugates were examined for their inhibitory effects toward rat and human liver microsomal N-dimethylnitrosoamine demethylase (NDMAd) activity using a radiometric NDMAd assay. Substrate concentrations of 30 and 60 μM were used to probe the activity of cytochrome P4502E1 isozyme through the α-hydroxylation of NDMA. It was found that alkyl Isothiocyanates such as sulforaphane and allyl isothiocyanate displayed very weak inhibition, whereas the arylalkyl Isothiocyanates such as benzyl and phenethyl isothiocyanate showed significant inhibition toward rat liver NDMAd activity with IC50 values of 9.0 and 8.3 μM, respectively. More interestingly, glutathione conjugates of benzyl, phenethyl, and 6-phenylhexyl Isothiocyanates all inhibited NDMAd at the comparable concentrations. In the phenethyl isothiocyanate conjugates series, there exist marked differences in their inhibitory activity; i.e., its conjugates with l-cysteine (IC50 = 4.3 μM) and with glutathione (IC5...
Stephen S Hecht - One of the best experts on this subject based on the ideXlab platform.
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phenethyl isothiocyanate and sulforaphane and their n acetylcysteine conjugates inhibit malignant progression of lung adenomas induced by tobacco carcinogens in a j mice
2005Co-Authors: Clifford C Conaway, Chung Xiou Wang, Brian Pittman, Yang Ming Yang, Joel E Schwartz, Defa Tian, Edward J Mcintee, Stephen S Hecht, Funglung ChungAbstract: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 post-initiation 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 micromol benzo(a)pyrene [B(a)P] and 3 micromol 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 +/- 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 of apoptosis (terminal nucleotidyl transferase-mediated nick end labeling and caspase-3) were observed in the isothiocyanate and isothiocyanate-N-acetylcysteine-treated groups that showed inhibition of the development of lung adenocarcinomas. The results of the study provide a basis for future evaluation of the potential of phenethyl isothiocyanate and sulforaphane and their conjugates as chemopreventive agents in smokers and ex-smokers with early lung lesions.
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effects of benzyl isothiocyanate and phenethyl isothiocyanate on dna adduct formation by a mixture of benzo a pyrene and 4 methylnitrosamino 1 3 pyridyl 1 butanone in a j mouse lung
2002Co-Authors: Kristina R K Sticha, Patrick M J Kenney, Gunnar Boysen, Hong Liang, Mingyao Wang, Pramod Upadhyaya, Stephen S HechtAbstract:Dietary phenethyl isothiocyanate (PEITC) and a mixture of dietary PEITC and benzyl isothiocyanate (BITC) inhibit lung tumorigenesis in A/J mice induced by a mixture of the tobacco smoke carcinogens benzo[a]pyrene (B[a]P) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In this study, we tested the hypothesis that inhibition of tumorigenesis by these Isothiocyanates was due to inhibition of DNA adduct formation. We quantified the following pulmonary DNA adducts: N 2 -[7,8,9-trihydroxy-7,8,9,10tetrahydrobenzo[a]pyrene-10-yl]deoxyguanosine (BPDEN 2 -dG) from B[a]P; and O 6 -methylguanine (O 6 -mG) and 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)-releasing adducts from NNK. Initial experiments demonstrated that there were no effects of B[a]P on NNK‐DNA adduct formation, or vice versa, and established by way of a time course study the appropriate sacrifice intervals for the main experiment. Dietary PEITC, or dietary BITC plus PEITC, inhibited the formation of HPB-releasing DNA adducts of NNK at several of the time points examined. There were no effects of dietary Isothiocyanates on levels of O 6 -mG or BPDEN 2 -dG. These results, which are consistent with previous studies in rats and with tumor inhibition data in mice, support a role for inhibition of HPB-releasing DNA adducts of NNK as a mechanism of inhibition of tumorigenesis by dietary PEITC and BITC plus PEITC. However, the observed inhibition was modest, suggesting that other effects of Isothiocyanates are also involved in chemoprevention in this model.
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inhibition of carcinogenesis by Isothiocyanates
2000Co-Authors: Stephen S HechtAbstract:Isothiocyanates occur as conjugates in a wide variety of cruciferous vegetables. Consumption of normal amounts of these vegetables results in the uptake of substantial quantities of Isothiocyanates. These naturally occurring Isothiocyanates as well as many synthetic analogs can be powerful inhibitors of carcinogenesis in laboratory animals. Particularly impressive results have been obtained in animal models of lung and esophageal cancer. This review summarizes available data on inhibition of carcinogenesis by Isothiocyanates. The major mechanism of inhibition appears to be selective inhibition of cytochrome P450 enzymes involved in carcinogen metabolic activation. Evidence for this is reviewed. Isothiocyanates also induce Phase II enzymes and enhance apoptosis. These properties may also be involved in their chemopreventive activity. Phenethyl isothiocyanate is a particularly effective inhibitor of lung tumor induction by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and, therefore, is currently being developed as a chemopreventive agent against lung cancer.
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chemoprevention of cancer by Isothiocyanates modifiers of carcinogen metabolism
1999Co-Authors: Stephen S HechtAbstract:Substantial quantities of Isothiocyanates are released upon consumption of normal amounts of a number of cruciferous vegetables. Some of these naturally occurring Isothiocyanates such as phenethyl isothiocyanate (PEITC), benzyl isothiocyanate (BITC) and sulforaphane are effective inhibitors of cancer induction in rodents treated with carcinogens. A large amount of data demonstrate that Isothiocyanates act as cancer chemopreventive agents by favorably modifying carcinogen metabolism via inhibition of Phase 1 enzymes and/or induction of Phase 2 enzymes. These effects are quite specific, depending on the structure of the isothiocyanate and carcinogen. One of the most thoroughly studied examples of isothiocyanate inhibition of rodent carcinogenesis is inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis by PEITC. This occurs because PEITC blocks the metabolic activation of NNK, resulting in increased urinary excretion of detoxified metabolites. Similar effects on NNK metabolism have been observed in smokers who consumed watercress, a source of PEITC. On the basis of these observations and knowledge of the carcinogenic constituents of cigarette smoke, a strategy for chemoprevention of lung cancer can be developed.
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chemoprevention by Isothiocyanates
1995Co-Authors: Stephen S HechtAbstract:Naturally occurring and synthetic Isothiocyanates are among the most effective chemopreventive agents known. A wide variety of Isothiocyanates prevents cancer in the rat lung, mammary gland, esophagus, liver, small intestine, colon, and bladder. Mechanistic studies have shown that this chemopreventive activity is due to favorable modification of phase I and phase II carcinogen metabolism, resulting in increased carcinogen excretion or detoxification and decreased carcinogen DNA interactions. Most studies reported that the isothiocyanate must be present at carcinogen exposure in order to effect tumorigenesis inhibition. Our studies focus on naturally occurring Isothiocyanates phenethyl isothiocyanate (PEITC) and benzyl isothiocyanate (BITC) as lung cancer inhibitors. These studies employed the major lung carcinogens in tobacco smoke, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo(a)pyrene (BaP). Combining chemopreventive agents that inhibit tumorigenesis by NNK and BaP in rodents may be effective in addicted smokers. PEITC inhibits lung tumor induction by NNK in F-344 rats and A/J mice, while BITC inhibits BaP-induced lung tumorigenesis in A/J mice; combining the two inhibits lung tumorigenesis by combined NNK and BaP in A/J mice. PEITC selectively inhibits metabolic activation of NNK in the rodent lung, while inducing glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), one of the major NNK metabolites. Thus, PEITC decreases DNA and hemoglobin adduct formation by NNK while increasing the amounts of NNAL and its glucuronide excreted in the urine. Presently available data indicate that non-toxic doses of PEITC can inhibit the metabolic activation and carcinogenicity of NNK in rat and mouse lung; BITC has similar effects on BaP activation and tumorigenicity in mouse lung. Thus, combinations of chemopreventive agents active against different carcinogens in tobacco smoke may be useful in the chemoprevention of lung cancer.
Paul Talalay - One of the best experts on this subject based on the ideXlab platform.
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urease from helicobacter pylori is inactivated by sulforaphane and other Isothiocyanates
2013Co-Authors: Jed W. Fahey, Kristina L Wade, Katherine K Stephenson, Paul TalalayAbstract:Infections by Helicobacter pylori are very common, causing gastroduodenal inflammation including peptic ulcers, and increasing the risk of gastric neoplasia. The isothiocyanate (ITC) sulforaphane [SF; 1-isothiocyanato-4-(methylsulfinyl)butane] derived from edible crucifers such as broccoli is potently bactericidal against Helicobacter, including antibiotic-resistant strains, suggesting a possible dietary therapy. Gastric H. pylori infections express high urease activity which generates ammonia, neutralizes gastric acidity, and promotes inflammation. The finding that SF inhibits (inactivates) urease (jack bean and Helicobacter) raised the issue of whether these properties might be functionally related. The rates of inactivation of urease activity depend on enzyme and SF concentrations and show first order kinetics. Treatment with SF results in time-dependent increases in the ultraviolet absorption of partially purified Helicobacter urease in the 260-320 nm region. This provides direct spectroscopic evidence for the formation of dithiocarbamates between the ITC group of SF and cysteine thiols of urease. The potencies of inactivation of Helicobacter urease by Isothiocyanates structurally related to SF were surprisingly variable. Natural Isothiocyanates closely related to SF, previously shown to be bactericidal (berteroin, hirsutin, phenethyl isothiocyanate, alyssin, and erucin), did not inactivate urease activity. Furthermore, SF is bactericidal against both urease positive and negative H. pylori strains. In contrast, some Isothiocyanates such as benzoyl-ITC, are very potent urease inactivators, but are not bactericidal. The bactericidal effects of SF and other ITC against Helicobacter are therefore not obligatorily linked to urease inactivation, but may reduce the inflammatory component of Helicobacter infections.
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chemoprotective glucosinolates and Isothiocyanates of broccoli sprouts metabolism and excretion in humans
2001Co-Authors: Theresa A Shapiro, Kristina L Wade, Katherine K Stephenson, Jed W. Fahey, Paul TalalayAbstract:Broccoli sprouts are a rich source of glucosinolates and Isothiocyanates that induce phase 2 detoxication enzymes, boost antioxidant status, and protect animals against chemically induced cancer. Glucosinolates are hydrolyzed by myrosinase (an enzyme found in plants and bowel microflora) to form Isothiocyanates. In vivo, Isothiocyanates are conjugated with glutathione and then sequentially metabolized to mercapturic acids. These metabolites are collectively designated dithiocarbamates. We studied the disposition of broccoli sprout glucosinolates and Isothiocyanates in healthy volunteers. Broccoli sprouts were grown, processed, and analyzed for (a) inducer potency; (b) glucosinolate and isothiocyanate concentrations; (c) glucosinolate profiles; and (d) myrosinase activity. Dosing preparations included uncooked fresh sprouts (with active myrosinase) as well as homogenates of boiled sprouts that were devoid of myrosinase activity and contained either glucosinolates only or Isothiocyanates only. In a crossover study, urinary dithiocarbamate excretion increased sharply after administration of broccoli sprout glucosinolates or Isothiocyanates. Cumulative excretion of dithiocarbamates following 111-mmol doses of Isothiocyanates was greater than that after glucosinolates (88.9 6 5.5 and 13.1 6 1.9 mmol, respectively; P < 0.0003). In subjects fed four repeated 50-mmol doses of Isothiocyanates, the intra- and intersubject variation in dithiocarbamate excretion was very small (coefficient of variation, 9%), and after escalating doses, excretion was linear over a 25- to 200-mmol dose range. Dithiocarbamate excretion was higher when intact sprouts were chewed thoroughly rather than swallowed whole (42.4 6 7.5 and 28.8 6 2.6 mmol; P 5 0.049). These studies indicate that Isothiocyanates are about six times more bioavailable than glucosinolates, which must first be hydrolyzed. Thorough chewing of fresh sprouts exposes the glucosinolates to plant myrosinase and significantly increases dithiocarbamate excretion. These findings will assist in the design of dosing regimens for clinical studies of broccoli sprout efficacy.
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human metabolism and excretion of cancer chemoprotective glucosinolates and Isothiocyanates of cruciferous vegetables
1998Co-Authors: Theresa A Shapiro, Kristina L Wade, Katherine K Stephenson, Jed W. Fahey, Paul TalalayAbstract:Isothiocyanates and their naturally occurring glucosinolate precursors are widely consumed as part of a diet rich in cruciferous vegetables. When plant cells are damaged, glucosinolates are released and converted to Isothiocyanates by the enzyme myrosinase. Many Isothiocyanates inhibit the neoplastic effects of various carcinogens at a number of organ sites. Consequently, these agents are attracting attention as potential chemoprotectors against cancer. As a prerequisite to understanding the mechanism of the protective effects of these compounds, which is thought to involve the modulation of carcinogen metabolism by the induction of phase 2 detoxication enzymes and the inhibition of phase 1 carcinogen-activating enzymes, we examined the fate of ingested Isothiocyanates and glucosinolates in humans. Recently developed novel methods for quantifying Isothiocyanates (and glucosinolates after their quantitative conversion to Isothiocyanates by purified myrosinase) and their urinary metabolites (largely dithiocarbamates) have made possible a detailed examination of the fates of Isothiocyanates and glucosinolates of dietary crucifers. In a series of studies in normal volunteers, we made these findings. First, in nonsmokers, urinary dithiocarbamates were detected only after the consumption of cruciferous vegetables and condiments rich in Isothiocyanates and/or glucosinolates. In sharp contrast, the consumption of noncrucifers (corn, tomatoes, green beans, and carrots) did not lead to the excretion of dithiocarbamates. Moreover, the quantities of dithiocarbamates excreted were related to the glucosinolate/isothiocyanate profiles of the cruciferous vegetables administered (kale, broccoli, green cabbage, and turnip roots). Second, eating prepared horseradish containing graded doses of Isothiocyanates (12.3-74 micromol; mostly allyl isothiocyanate) led to a rapid excretion of proportionate amounts (42-44%) of urinary dithiocarbamates with first-order kinetics. The ingestion of broccoli in which myrosinase had been heat-inactivated also led to proportionate but low (10-20%) recoveries of urinary dithiocarbamates. Broccoli samples subsequently treated with myrosinase to produce the cognate Isothiocyanates were much more completely (47%) converted to dithiocarbamates. Finally, when bowel microflora were reduced by mechanical cleansing and antibiotics, the conversion of glucosinolates became negligible. These results establish that humans convert substantial amounts of Isothiocyanates and glucosinolates to urinary dithiocarbamates that can be easily quantified, thus paving the way for meaningful studies of phase 2 enzyme induction in humans.
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mechanism of differential potencies of Isothiocyanates as inducers of anticarcinogenic phase 2 enzymes
1998Co-Authors: Yuesheng Zhang, Paul TalalayAbstract:Abstract 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 µm) of certain Isothiocyanates, the intracellular isothiocyanate/dithiocarbamate concentrations (measured by cyclocondensation with 1,2-benzenedithiol) rose rapidly (30 min at 37°C) to very high levels ( e.g. , 800–900 µm). 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 µm for 24 h at 37°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.
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mechanism of differential potencies of Isothiocyanates as inducers of anticarcinogenic phase 2 enzymes
1998Co-Authors: Yuesheng Zhang, Paul TalalayAbstract: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.
Christine M Munday - One of the best experts on this subject based on the ideXlab platform.
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inhibition of urinary bladder carcinogenesis by broccoli sprouts
2008Co-Authors: Rex Munday, Jed W. Fahey, Paulette Mhawechfauceglia, Christine M Munday, Joseph D Paonessa, Li Tang, John S Munday, Carolyn E Lister, Paula Wilson, Warren DavisAbstract:Isothiocyanates are a well-known class of cancer chemopreventive agents, and broccoli sprouts are a rich source of several Isothiocyanates. We report herein that dietary administration to rats of a freeze-dried aqueous extract of broccoli sprouts significantly and dose-dependently inhibited bladder cancer development induced by N-butyl-N-(4-hydroxybutyl) nitrosamine. The incidence, multiplicity, size, and progression of bladder cancer were all inhibited by the extract, while the extract itself caused no histologic changes in the bladder. Moreover, inhibition of bladder carcinogenesis by the extract was associated with significant induction of glutathione S-transferase and NAD(P)H:quinone oxidoreductase 1 in the bladder, enzymes that are important protectants against oxidants and carcinogens. Isothiocyanates are metabolized to dithiocarbamates in vivo, but dithiocarbamates readily dissociate to Isothiocyanates. We found that >70% of the Isothiocyanates present in the extract were excreted in the urine as isothiocyanate equivalents (Isothiocyanates + dithiocarbamates) in 12 h after a single p.o. dose, indicating high bioavailability and rapid urinary excretion. In addition, the concentrations of isothiocyanate equivalents in the urine of extract-treated rats were 2 to 3 orders of magnitude higher than those in plasma, indicating that the bladder epithelium, the major site of bladder cancer development, is most exposed to p.o. dosed isothiocyanate. Indeed, tissue levels of isothiocyanate equivalents in the bladder were significantly higher than in the liver. In conclusion, broccoli sprout extract is a highly promising substance for bladder cancer prevention and the Isothiocyanates in the extract are selectively delivered to the bladder epithelium through urinary excretion.
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induction of phase ii detoxification enzymes in rats by plant derived Isothiocyanates comparison of allyl isothiocyanate with sulforaphane and related compounds
2004Co-Authors: Rex Munday, Christine M MundayAbstract:Plants of the family Brassicaceae contain high levels of glucosinolates. The latter compounds are degraded to Isothiocyanates, some of which have been shown to be potent inducers of phase II detoxification enzymes in vitro. In the present study, the ability of six plant-derived Isothiocyanates (allyl isothiocyanate, iberverin, erucin, sulforaphane, iberin, and cheirolin) to increase tissue levels of the phase II detoxification enzymes quinone reductase (QR) and glutathione S-transferase (GST) in a variety of rat tissues has been compared. At the low dose level employed (40 μmol/kg/day), cheirolin was without effect in any tissue. All of the other Isothiocyanates, however, increased GST and QR activities in the duodenum, forestomach, and/or the urinary bladder of the animals, with the greatest effects being seen in the urinary bladder. With the exception of cheirolin, little difference was observed in the inductive activity of the various Isothiocyanates. Phase II enzymes are known to protect against chemi...
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induction of phase ii detoxification enzymes in rats by plant derived Isothiocyanates comparison of allyl isothiocyanate with sulforaphane and related compounds
2004Co-Authors: Rex Munday, Christine M MundayAbstract:Plants of the family Brassicaceae contain high levels of glucosinolates. The latter compounds are degraded to Isothiocyanates, some of which have been shown to be potent inducers of phase II detoxification enzymes in vitro. In the present study, the ability of six plant-derived Isothiocyanates (allyl isothiocyanate, iberverin, erucin, sulforaphane, iberin, and cheirolin) to increase tissue levels of the phase II detoxification enzymes quinone reductase (QR) and glutathione S-transferase (GST) in a variety of rat tissues has been compared. At the low dose level employed (40 micromol/kg/day), cheirolin was without effect in any tissue. All of the other Isothiocyanates, however, increased GST and QR activities in the duodenum, forestomach, and/or the urinary bladder of the animals, with the greatest effects being seen in the urinary bladder. With the exception of cheirolin, little difference was observed in the inductive activity of the various Isothiocyanates. Phase II enzymes are known to protect against chemical carcinogenesis, and the selectivity of Isothiocyanates in inducing such enzymes in the bladder is of interest in view of recent epidemiological studies showing a decreased incidence of cancer of this organ in individuals with a high dietary intake of Brassica vegetables.
Daniel G. Vassão - One of the best experts on this subject based on the ideXlab platform.
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the phytopathogenic fungus sclerotinia sclerotiorum detoxifies plant glucosinolate hydrolysis products via an isothiocyanate hydrolase
2020Co-Authors: Jingyuan Chen, Franziska Beran, Jonathan Gershenzon, Michael Reichelt, Chhana Ullah, Zhiling Yang, Almuth Hammerbacher, Daniel G. VassãoAbstract:Brassicales plants produce glucosinolates and myrosinases that generate toxic Isothiocyanates conferring broad resistance against pathogens and herbivorous insects. Nevertheless, some cosmopolitan fungal pathogens, such as the necrotrophic white mold Sclerotinia sclerotiorum, are able to infect many plant hosts including glucosinolate producers. Here, we show that S. sclerotiorum infection activates the glucosinolate-myrosinase system, and Isothiocyanates contribute to resistance against this fungus. S. sclerotiorum metabolizes Isothiocyanates via two independent pathways: conjugation to glutathione and, more effectively, hydrolysis to amines. The latter pathway features an isothiocyanate hydrolase that is homologous to a previously characterized bacterial enzyme, and converts isothiocyanate into products that are not toxic to the fungus. The isothiocyanate hydrolase promotes fungal growth in the presence of the toxins, and contributes to the virulence of S. sclerotiorum on glucosinolate-producing plants.
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the phytopathogenic fungus sclerotinia sclerotiorum detoxifies plant glucosinolate hydrolysis products via an isothiocyanate hydrolase
2020Co-Authors: Jingyuan Chen, Franziska Beran, Jonathan Gershenzon, Michael Reichelt, Chhana Ullah, Zhiling Yang, Almuth Hammerbacher, Daniel G. VassãoAbstract:Brassicales plants produce glucosinolates and myrosinases that generate toxic Isothiocyanates conferring broad resistance against pathogens and herbivorous insects. Nevertheless, some cosmopolitan fungal pathogens, such as the necrotrophic white mold Sclerotinia sclerotiorum, are able to infect many plant hosts including glucosinolate producers. Here, we show that S. sclerotiorum infection activates the glucosinolate-myrosinase system, and Isothiocyanates contribute to resistance against this fungus. S. sclerotiorum metabolizes Isothiocyanates via two independent pathways: conjugation to glutathione and, more effectively, hydrolysis to amines. The latter pathway features an isothiocyanate hydrolase that is homologous to a previously characterized bacterial enzyme, and converts isothiocyanate into products that are not toxic to the fungus. The isothiocyanate hydrolase promotes fungal growth in the presence of the toxins, and contributes to the virulence of S. sclerotiorum on glucosinolate-producing plants. Some plants produce toxic Isothiocyanates that protect them against pathogens. Here, Chen et al. show that the plant pathogenic fungus Sclerotinia sclerotiorum converts Isothiocyanates into non-toxic compounds via glutathione conjugation and, more effectively, via hydrolysis to amines using an isothiocyanate hydrolase.
