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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Indole-3-carbinol (I3C), a natural compound from cruciferous vegetables, inhibits aflatoxin B1 (AFB1) carcinogenesis in trout when administered prior to and during carcinogen exposure, but also promotes it in the same species when given after AFB1 initiation. To provide quantitative potency information for these opposing activities, detailed tumor dose-response studies were performed with AFB1 (10-400 ppb) and I3C (0-4,000 ppm). In a plot of (logit) percent tumor response vs log AFB1 exposure, the results generated a series of parallel AFB1 dose-response curves. Increasing I3C doses displaced these curves, respectively, toward higher and lower AFB1 doses in the inhibition and promotion studies. Similar potencies were observed over the dose range 0-1,500 ppm I3C; the 50% promotion and inhibition (P50 and I50) values were 1,000 vs 1,400 ppm I3C, respectively. Differences in the protocols used in the two studies suggest that the inhibitory activity of I3C is more likely to supersede promotion under human exposure conditions.
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PMID:Tumor dose-response studies with aflatoxin B1 and the ambivalent modulator indole-3-carbinol: inhibitory versus promotional potency. 210 97

It is known that consumption of cruciferous vegetables protects against the chemical induction of cancer in many organs. It has been suggested that this protection is mediated through an effect on the cytochrome P450 monooxygenase system. This system is responsible for the activation of a number of chemical carcinogens to their ultimate forms. In the present study, the effect of indole-3-carbinol (I3C) and 5,6-benzoflavone (5,6BF) on the expression of cytochrome P450IA1 in rat colon and liver has been investigated. Cytochrome P450IA1 mRNA was induced in colon following a single oral administration of I3C or 5,6BF. A biphasic induction profile was obtained with maxima at 4 and 16 h post-administration. Both inducers caused an approximately 2-fold increase in P450IA1 mRNA at 4 h and a 10-fold increase at 16 h. In contrast, both cytochrome P450IA1 and IA2 mRNAs was increased over the control between 4 and 24 h. The total amount of P450IA mRNAs in liver at 4 and 16 h was increased about 2- and 4-fold respectively by I3C; 5,6BF induced the P450IA mRNAs 4- and 5-fold respectively. The expression of cytochrome P450IA1 and IA2 is induced by I3C and several flavones present in cruciferous vegetables. This suggests that one of the protective effects of cruciferous vegetables in the reduction of chemically induced cancer may be regulation of cytochrome P450s involved in the metabolism of the chemical carcinogens.
Carcinogenesis 1990 Aug
PMID:Induction of cytochrome P450IA1 in rat colon and liver by indole-3-carbinol and 5,6-benzoflavone. 238 12

The modifying effects of sinigrin (Sin) and indole-3-carbinol (I3C) on the hepatocarcinogenesis induced by diethylnitrosamine (DEN) were investigated in male ACI/N rats. Rats were divided into six groups: group 1 was given DEN (40 p.p.m.) in the drinking water for 5 weeks, starting at 7 weeks of age; group 2 was treated with DEN and diet containing 1200 p.p.m. Sin; group 3 received DEN and diet containing 1000 p.p.m. I3C; group 4 was given Sin diet alone; group 5 was given I3C diet alone; and group 6 served as controls. The diet containing Sin or I3C was fed to the rats starting at 6 weeks of age until 1 week after the carcinogen exposure. At termination of the experiment (week 29), the incidences of iron-excluding altered foci (11.22 +/- 3.22/cm2) and liver cell tumors (6/12, 50%) and the tumor multiplicity (0.9/rat) in rats of group 2 were significantly smaller than those of group 1 (foci incidence, 48.33 +/- 6.34/cm2, tumor incidence, 10/10, 100%; multiplicity, 9.5/rat) (P less than 0.02). Similarly, the incidence of iron-excluding hepatocellular foci (17.65 +/- 4.67/cm2) and tumor multiplicity (2.4/rat) with a slight reduction of tumor incidence (9/12, 75%) in rats of group 3 were significantly lower than those of group 1 (P less than 0.001). There were no liver cell neoplasms in rats of groups 4, 5 and 6. Thus, Sin and I3C inhibited the hepatocarcinogenesis induced by DEN when they were administered concurrently with the carcinogen.
Carcinogenesis 1990 Aug
PMID:Inhibitory effect of sinigrin and indole-3-carbinol on diethylnitrosamine-induced hepatocarcinogenesis in male ACI/N rats. 238 27

In this review, some common food plants and their toxic or otherwise bioactive components and mycotoxin contaminants have been considered. Crucifers contain naturally occurring components that are goitrogenic, resulting from the combined action of allyl isothiocyanate, goitrin, and thiocyanate. Although crucifers may provide some protection from cancer when taken prior to a carcinogen, when taken after a carcinogen they act as promoters of carcinogenesis. The acid-condensed mixture of indole-3-carbinol (a component of crucifers) binds to the TCDD receptor and causes responses similar to those of TCDD. Herbs contain many biologically active components, with more than 20% of the commercially prepared human drugs coming from these plants. Onion and garlic juices can help to prevent the rise of serum cholesterol. Most herbs used in treatments may have many natural constituents that act oppositely from their intended use. Some herbs like Bishop's week seed contain carcinogens, and many contain pyrrolizidine alkaloids that can cause cirrhosis of the liver. The general phytoalexin response in plants (including potatoes, tomatoes, peppers, eggplant, celery, and sweet potatoes) induced by external stimuli can increase the concentrations of toxic chemical constituents in those plants. In potatoes, two major indigenous compounds are alpha-solanine and alpha-chaconine, which are human plasma cholinesterase inhibitors and teratogens in animals. Because of its toxicity, the potato variety Lenape was withdrawn from the market. Celery, parsley, and parsnips contain the linear furanocoumarin phytoalexins psoralen, bergapten, and xanthotoxin that can cause photosensitization and also are photomutagenic and photocarcinogenic. Celery field workers and handlers continually have photosensitization problems as a result of these indigenous celery furanocoumarins. A new celery cultivar (a result of plant breeding to produce a more pest-resistant variety) was responsible for significant incidences of phytophotodermatitis of grocery employees. Since there is no regulatory agency or body designated to oversee potential toxicological issues associated with naturally occurring toxicants, photodermatitis continues to occur from celery exposure. Sweet potatoes contain phytoalexins that can cause lung edema and are hepatotoxic to mice. At least one of these, 4-ipomeanol, can cause extensive lung clara cell necrosis and can increase the severity of pneumonia in mice. Some phytoalexins in sweet potatoes are hepatotoxic and nephrotoxic to mice. The common mushroom Agaricus bisporus contains benzyl alcohol as its most abundant volatile, and A. bisporus and Gyromitra esculenta both contain hydrazine analogues. Mycotoxins are found in corn, cottonseed, fruits, grains, grain sorghums, and nuts (especially peanuts); therefore, they also occur in apple juice, bread, peanut butter, and other products made from contaminated starting materials.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Natural pesticides and bioactive components in foods. 240 25

A number of recent studies have described inhibitor-mediated reductions in the covalent DNA binding and tumorigenicity of various carcinogens, in species such as rats, mice and rainbow trout (Salmo gairdneri). Since inhibitory effects have, in most cases, been reported after testing at one carcinogen and one inhibitor level only, the detailed relationships between carcinogen dose, inhibitor dose, in vivo DNA binding and final tumor response are not well understood in any species. To determine these relationships we have employed the trout model in a combined DNA binding/tumor dose-response protocol using approximately 10,000 animals. Trout were pretreated with one of five different dose-levels of indole-3-carbinol (I3C), a naturally occurring anti-carcinogen found in cruciferous vegetables such as broccoli and cabbage. After 4 weeks, animals received the same dietary level of I3C for a further 2 weeks together with [3H]aflatoxin B1 (AFB1) in the dose-range 10-320 p.p.b. From tanks containing 150 animals (three tanks per I3C-AFB1 dose-point), 15 fish were selected at random in order to assess hepatic AFB1-DNA binding levels. Remaining animals were returned to control diet for determination of tumor response at 12 months. Linear increases in DNA binding occurred with dose of AFB1 at each I3C dose-level. Successive increases in I3C dose gave dose-related decreases in AFB1-DNA binding, resulting in a series of curves of decreasing slope. Shifts in DNA-binding slopes were compared quantitatively with horizontal displacements towards higher carcinogen dose in corresponding tumor dose-response curves. At I3C doses of less than or equal to 2000 p.p.m., the inhibitor-altered tumor response was predicted precisely by changes in dose received (DNA adducts formed) in the target organ. These data constitute the first direct evidence of pure anti-initiating activity by a natural anti-carcinogen found in human diet, where all animals were treated at the same time and under identical conditions of exposure in both DNA binding and tumor studies. The data are discussed further in view of (i) their implications for DNA binding-carcinogenicity correlations and the concept of 'molecular dosimetry', and (ii) limitations in the current database on anti-carcinogenesis as regards in vivo potency information, particularly for 'ambivalent modulators' which exhibit both inhibitory and promotional activity.
Carcinogenesis 1989 Jan
PMID:Quantitative inter-relationships between aflatoxin B1 carcinogen dose, indole-3-carbinol anti-carcinogen dose, target organ DNA adduction and final tumor response. 249 68

The effects of dietary Brussels sprouts and indole-3-carbinol (I3C) on xenobiotic-metabolizing enzyme activities and hepatic aflatoxin B1 (AFB1)-DNA binding were determined in rats. Animals were dosed intraperitoneally (i.p.) or intragastrically (i.g.) with [3H]AFB1 and killed 2 (i.p.) or 3 (i.g.) h later. Brussels sprouts caused a significant (P less than 0.01) 50-60% decrease in hepatic AFB1-DNA binding, and increased hepatic and intestinal glutathione S-transferase (GST) activities. Hepatic mono-oxygenase (AHH and ECD) activities were not altered in sprouts-fed rats, but greater than 2-fold increases in intestinal AHH and ECD activities were found. Although I3C increased intestinal AHH and ECD activities similarly to Brussels sprouts, I3C did not significantly decrease AFB1 binding, nor did it increase hepatic or intestinal GST activity. Route of administration did not alter the percentage inhibition of binding in comparison to control rats in either treatment group, suggesting that the small intestine may not play a significant role in the metabolism of AFB1. In a second experiment, rats were dosed either i.p. or i.g. with [3H]AFB1 and killed 2, 6, 12, 24 or 48 h later. Hepatic AFB1-DNA binding and tissue radioactivity levels were determined. Brussels sprouts once again significantly (P less than 0.001) decreased hepatic AFB1-DNA binding. Route of administration of the carcinogen did not affect DNA binding over time in sprouts-fed animals, confirming our previous results.
Carcinogenesis 1989 Apr
PMID:Effect of diet and route of administration on the DNA binding of aflatoxin B1 in the rat. 270 10

Indole-3-carbinol (I3C), a compound found naturally as a glucosinolate in cruciferous vegetables such as broccoli and cabbage, has been shown to modulate the carcinogenic process in a number of animal species. The lack of detailed information on the disposition of I3C in vivo provided the main impetus for the study reported here, in which the distribution and metabolic fate of I3C was assessed in selected tissues and excreta after po administration to rainbow trout (Salmo gairdneri). Animals were fasted for 3 days and given [5-3H]I3C either in the diet or by single oral gavage (40 mg/kg body weight; 15 muCi/kg body weight). Following administration, 75% of the initial 3H-dose was detected within the stomach between 0.5 and 12 hr, after which it was released to distal regions of the gut for subsequent uptake, distribution and elimination. At the end of the study (72 hr) 25% of the administered dose was recovered from the water which reflected excretion through the gills and urinary tract. Significant excretion also occurred in the bile, with approximately 5% of the initial 3H-dose recovered from the bile sacs at 72 hr. Further analyses of the radioactive components in the bile indicated that one or more derivatives of I3C, but not the parent compound itself, are excreted as glucuronide conjugates using this route. Radioactivity accumulated in the liver throughout most of the study, reaching levels of 1-1.5% between 48 and 72 hr of the administered dose. High-performance liquid chromatography analyses indicated the presence of four main radiolabelled species in these livers, one of which co-eluted with the parent compound, I3C. The major radiolabelled species recovered from the liver was tentatively identified as the dimer, 3,3'-diindolylmethane (I33'), which comprised 40% of the total hepatic radiolabel. This dimer, I33', was also found to accumulate in the diet containing I3C, which reflected a time-dependent dimerization of the parent compound in vitro. These findings are discussed in view of recent postulates of a role for I3C condensation products such as I33' in the mechanism of I3C anti-carcinogenesis.
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PMID:In vivo disposition of the natural anti-carcinogen indole-3-carbinol after po administration to rainbow trout. 279 68

In a study designed to investigate the effects of dietary synergisms on 1,2-dimethylhydrazine (DMH)-induced rat colon carcinogenesis, fecal pellets were examined for the presence of direct-acting fecal mutagens and levels of Bacteroides fragilis group organisms. Intraperitoneal injections of DMH at 10 mg/kg were given for 16 weeks (weeks 3-18) to 160 male F344 rats consuming 4 supplemental dietary factors in all possible combinations. The dietary factors examined were wheat bran (15%), cholesterol (1%), beef tallow (18%) and indole-3-carbinol (IC) (0.1%). Feces were collected 3, 10, 17, 24 and 31 weeks after commencing the dietary treatments and dichloromethane extracts were assayed using the Salmonella typhimurium TA100 without metabolic activation. The numbers of B. fragilis group organisms were enumerated in feces collected at the same time. Most feces samples were negative for mutagens but extracts from weeks 17-31 showed a significant mutagenic response from the IC factor in the diet. The fecal levels of B. fragilis were significantly increased by the inclusion of cholesterol in the diets. The B. fragilis counts and fecal mutagen production were not correlated (r = 0.09), although species of the B. fragilis group have been implicated in the production on human fecal mutagens.
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PMID:Fecal mutagens and Bacteroides fragilis levels in the feces of dimethylhydrazine-treated rats: influence of diet. 299 2

Indole-3-carbinol (I3C), a component of cruciferous vegetables, was previously shown to inhibit aflatoxin B1 (AFB1) carcinogenesis in trout. The purpose of this study was to examine the effect of I3C on AFB1 metabolism and hepatic DNA adduct formation in vivo and in vitro. When fed at 0.2%, I3C produced a 70% reduction in average in vivo hepatic DNA binding of injected AFB1 over a 21-day period when compared to controls. A 24-h distribution study of injected tritiated AFB1 in I3C fish showed less total radioactivity in the blood and liver at all times examined, compared to controls. These reductions were due primarily to reduced levels of AFB1 bound to red blood cell DNA, reduced plasma levels of the primary metabolite aflatoxicol (AFL), and decreased levels of AFB1 and polar metabolites present in the liver of I3C fish. In contrast to blood, total radioactivity was significantly elevated in the bile of I3C fish resulting from a 7-fold increase in aflatoxicol-M1 glucuronide levels over controls. No difference was observed in concentration of AFL glucuronide, the primary conjugate present in control fish. There was no difference in total radioactivity remaining in the carcass of I3C or control fish. AFB1 metabolism in freshly isolated hepatocytes from I3C fish showed 20% less DNA binding in a 1-h assay, with a 2-fold increase in aflatoxin M1 production. Addition of I3C to control hepatocytes at levels of 1, 10 or 100 microM had no effect on AFB1 DNA binding. These findings indicate that I3C inhibition of AFB1 hepatocarcinogenesis in trout involves substantial changes in the pharmacokinetics of carcinogen distribution, metabolism and elimination, leading to significantly reduced initial hepatic-nuclear DNA damage in vivo.
Carcinogenesis 1986 Dec
PMID:Mechanisms of anti-carcinogenesis by indole-3-carbinol: effect on the distribution and metabolism of aflatoxin B1 in rainbow trout. 309 88

Indole-3-carbinol (I3C), a natural constituent of cruciferous vegetables, is an inhibitor in several experimental animal models of carcinogenesis by polynuclear aromatic hydrocarbons or aflatoxin B1 (AFB1) when administered prior to or during carcinogen exposure. For assessment of the postinitiation effects of I3C, rainbow trout were exposed to dietary I3C in two different protocols--before and during AFB1 exposure or after AFB1 exposure only. Preinitiation exposure to I3C reduced AFB1-initiated hepatocellular carcinomas in trout as previously reported, but post-initiation I3C exposure strongly enhanced the tumor incidence above the positive AFB1 control. These results reveal the need for additional research to elucidate the overall effect of I3C on chemical carcinogenesis.
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PMID:Enhancement of carcinogenesis by the natural anticarcinogen indole-3-carbinol. 310 95


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