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1.
Glutathione (GSH) S-transferase is a major detoxification enzyme system that catalyzes the binding of a variety of electrophiles, including reactive forms of chemical carcinogens, to GSH. Green coffee beans fed in the diet induced increased GSH S-transferase activity in the mucosa of the small intestine and in the liver of mice. A potent compound that induces increased GSH S-transferase activity was isolated from green coffee beans and identified as kahweol palmitate. The corresponding free alcohol, kahweol, and its synthetic monoacetate are also potent inducers of the activity of GSH S-transferase. A similar diterpene ester, cafestol palmitate, isolated from green coffee beans was active but less so than was kahweol palmitate. Likewise, the corresponding alcohol, cafestol, and its monoacetate showed moderate potency as inducers of increased GSH S-transferase activity. Kahweol palmitate and cafestol palmitate were extracted from green coffee beans into petroleum ether. The petroleum ether extract was fractionated by preparative normal-phase and reverse-phase liquid chromatographies successively. Final purification with silver nitrate-impregnated thin-layer chromatography yielded the pure palmitates of cafestol and kahweol. The structures were determined by examination of the spectroscopic data of the esters and their parent alcohols and by derivative comparison. 相似文献
2.
Pokharel YR Han EH Kim JY Oh SJ Kim SK Woo ER Jeong HG Kang KW 《Carcinogenesis》2006,27(12):2483-2490
Typically chemopreventive agents either induce phase II detoxifying enzymes or inhibit the cytochrome P450 enzymes (CYPs) that are required for the metabolism of carcinogens. In this study, we isolated a coumarin compound, isoimperatorin from Poncirus trifoliata Raf., and studied its protective effects against aflatoxin B1 (AFB1)-induced cytotoxicity in H4IIE cells. Isoimperatorin (>0.3 microM) significantly inhibited the cytotoxic effect of AFB1. CDNB [1-chloro-2,4-dinitrobenzene; glutathine S-transferase (GST) subtype-non-specific] and NBD (7-chloro-4-nitrobenzo-2-oxa-1,3-diazole; GSTalpha type-specific) assays revealed that isoimperatorin (0.3-3 microM) increased GST activity in a concentration-dependent manner. Western blot analyses using subtype-specific antibodies confirmed that GSTalpha protein, but not GSTmu or GSTpi, was induced in cells treated with isoimperatorin. Reporter gene analysis using an antioxidant response element (ARE) containing construct and subcellular fractionation assays revealed that GSTalpha induction by isoimperatorin is associated with Nrf2/ARE activation. Moreover, ethoxyresorufin-O-deethylase assays showed that isoimperatorin (2 microM) completely inhibited 3-methylchoranthrene-inducible CYP1A activity. These results indicate that isoimperatorin from Poncirus trifoliata Raf. possesses a potent hepatoprotective effect against AFB1, presumably through the induction of GSTalpha and the direct inhibition of CYP1A, and suggest that isoimperatorin should be considered a potential chemopreventive. 相似文献
3.
The expression of immunoreactive glutathione S-transferase (GST) was examined in hepatic neoplasms induced in rainbow trout by aflatoxin B1 (AFB) or 1,2-dimethylbenzanthracene (DMBA). Tumors were induced in adult trout by continuous dietary exposure to 8 p.p.b. AFB1 for 12 months or embryo bath exposure to DMBA (5 p.p.m. for 24 h, 3 times with 12 h intervals between exposures). Polyclonal antiserum specific for the two major trout hepatic GST subunits in trout liver was produced by immunizing rabbits with affinity-purified trout GST. Hepatocellular, cholangiolar and mixed neoplasms as well as foci of hepatocellular alteration were examined for GST immunoreactivity by the PAP technique. The majority of lesions were GST-deficient (AFB treated, 67%; DMBA treated, 54%), whereas GST expression was induced in 21% (AFB treated) and 31% (DMBA treated) of altered hepatic foci. The GST-induced foci were consistently small (AFB treated, 0.07 +/- 0.05 mm2; DMBA treated, 0.02 +/- 0.01 mm2) and none had progressed beyond the altered focus stage. The majority of larger advanced lesions (adenomas and carcinomas) were GST deficient (AFB treated, 2.33 +/- 0.35 mm2; DMBA treated, 2.95 +/- 0.59 mm2). These studies demonstrate that induced GST expression occurs in some small populations of hepatocytes, but not in larger advanced stages of malignant progression of aflatoxin- or PAH-induced hepatic neoplasms in rainbow trout. 相似文献
4.
Schilter BenoIt; Perrin Irene; Cavin Christophe; Huggett Anthony C. 《Carcinogenesis》1996,17(11):2377-2384
The coffee specific diterpenes cafestol and kahweol (C + K)have been reported to be anti-carcinogenic in several animalmodels. It has been postulated that this activity may be relatedto their ability to induce glutathione S-transferases (GSTs).We investigated the influence of a mixture of C + K, incorporatedat various levels in the diet of SpragueDawley rats,on the expression of different hepatic GST iso-enzymes. Liversamples were examined using isoform-specific GST substratesand antibodies, and highly selective oligomers were employedto determine effects at the RNA level. A dose-dependent increasein general GST activity was observed in male and female animalsfollowing 28 or 90 days of treatment. A time-course study demonstratedthat the maximal effect was observed within 5 days of treatment.Little or no effect was found on the activity of GST alpha andmu iso-enzymes. The most striking observation was a dose-dependentinduction of placental glutathione S-transferase (GST-P) whichcould be demonstrated at the mRNA, protein and enzymatic levels.This effect was observed in both male and female rats. The maximalinduction was attained within 5 days of treatment with C + K,remained elevated with continued treatment, but was reversibleon withdrawal of treatment. Immuno-histochemical examinationof liver slices revealed a strong even distribution of GST-Pexpression throughout the acinus at the highest dose of C +K, while at lower doses the induction of GST-P occurred predominantlyin periportal hepatocytes. There was no indication of the presenceof preneoplastic foci and, furthermore, the effect of C + Kon the GST-P was completely reversible. These findings indicatethat the anticarcinogenic mechanism of C + K may involve a specificinduction of GST-P and suggest a potential role for GST-P indetoxifying carcinogenic compounds. 相似文献
5.
Previous studies have shown that dietary R-goitrin is a potentinducer of hepatic glutathione S-transferase (GST) and epoxidehydrolase activities but has no effect on components of themixed function oxidase system (ethoxycoumarin O-deethylase andcytochrome P-450). In the present work effects of dietary R-goitrin(200 p.p.m.) or butylated hydroxyanisole (BHA) (7500 p.p.m.)on GST activity, binding of aflatoxin B1, (AFB]) to DNA, invivo, and biliary excretion of thiol conjugates of AFB1 in ratswere studied. Increases of GST activities (1.9- and 2.1-fold)were accompanied by reductions in AFB1-DNA binding (43% and85%) and increases (1.7-and 2.2-fold) in biliary excretion ofAFB1-thiol conjugates in R-goitrin and BHA groups, respectively.Microsomal aflatoxin 8,9-epoxidase activities were not increasedin either treatment group. The role of GST induction in thecarcinogenesis of AFB1 and the anticarcinogenic potential ofR-goitrin are discussed. 相似文献
6.
Mechanisms of protection against aflatoxin B(1) genotoxicity in rats treated by organosulfur compounds from garlic 总被引:2,自引:0,他引:2
Diallyl sulfide (DAS) and diallyl disulfide (DADS), two garlic constituents, were found previously to inhibit aflatoxin B(1) (AFB(1))-initiated carcinogenesis in rat liver, DADS being the most effective. In order to study the mechanisms involved in this protection, we have examined the ability of liver microsomes and cytosols from DAS- and DADS-treated rats to modulate the mutagenicity and the metabolism of AFB(1). We also examined the effects of these compounds on the expression of cytochromes P450 (CYP) and phase II enzymes known to be involved in AFB(1) metabolism. Administration of DAS (1 mmol/kg for 4 days) to rats resulted in significant inhibition of microsome-mediated mutagenicity of AFB(1), whereas DADS treatment did not alter AFB(1) mutagenicity. DAS treatment increased the metabolism of AFB(1) mainly towards the formation of AFQ(1) and AFM(1), which might account for the reduction of AFB(1) microsomal-mediated mutagenicity. DADS treatment slightly affected the oxidative metabolism of AFB(1). DAS and DADS induced CYP3A2, CYP2B1 and CYP2B2, DAS being more potent. Cytosols from DAS- and DADS-treated rats produced a significant inhibition of AFB(1)-8,9-epoxide (AFBO)-induced mutagenicity and significantly increased the cytosolic formation of AFB(1)-glutathione conjugates, DADS treatment being more effective. Western blot analysis showed that DADS is a potent inducer of glutathione S-transferase A5 (rGSTA5) and AFB(1) aldehyde reductase 1 (rAFAR1), while DAS is a weak inducer of these enzymes. Finally, we demonstrated that antibodies raised against rGSTA5 strongly reduced the antimutagenic activity of cytosols from DAS- and DADS-treated rats against AFBO. All together, these results demonstrate that DAS prevents AFB(1) mutagenicity through a dual mechanism, i.e. by modulating both the phase I and II metabolism of AFB(1), whereas DADS acts mainly by increasing the phase II metabolism of AFB(1). The induction of rGSTA5 and rAFAR1 is probably the main mechanism by which allyl sulfides give protection against AFB(1)-induced carcinogenesis. 相似文献
7.
Identification of differentially expressed genes in aflatoxin B1- treated cultured primary rat hepatocytes and Fischer 344 rats 总被引:4,自引:1,他引:4
Harris AJ; Shaddock JG; Manjanatha MG; Lisenbey JA; Casciano DA 《Carcinogenesis》1998,19(8):1451-1458
Aflatoxin B1 (AFB1), a mutagen and hepatocarcinogen in rats and humans, is
a contaminant of the human food supply, particularly in parts of Africa and
Asia. AFB1-induced changes in gene expression may play a part in the
development of the toxic, immunosuppressive and carcinogenic properties of
this fungal metabolite. An understanding of the-role of AFB1 in modulating
gene regulation should provide insight regarding mechanisms of AFB1-induced
carcinogenesis. We used three PCR- based subtractive techniques to identify
AFB1-responsive genes in cultured primary rat hepatocyte RNA: differential
display PCR (DD-PCR), representational difference analysis (RDA) and
suppression subtractive hybridization (SSH). Each of the three techniques
identified AFB1- responsive genes, although no individual cDNA was isolated
by more than one technique. Nine cDNAs isolated using DD-PCR, RDA or SSH
were found to represent eight genes that are differentially expressed as a
result of AFB1 exposure. Genes whose mRNA levels were increased in cultured
primary rat hepatocytes after AFB1 treatment were corticosteroid binding
globulin (CBG), cytochrome P450 4F1 (CYP4F1), alpha-2 microglobulin,
C4b-binding protein (C4BP), serum amyloid A-2 and glutathione S-transferase
Yb2 (GST). Transferrin and a small CYP3A-like cDNA had reduced mRNA levels
after AFB1 exposure. Full-length CYP3A mRNA levels were increased. When
liver RNA from AFB1-treated male F344 rats was evaluated for transferrin,
CBG, GST, CYP3A and CYP4F1 expression, a decrease in transferrin mRNA and
an increase in CBG, GST, CYP3A and CYP4F1 mRNA levels was also seen.
Analysis of the potential function of these genes in maintaining cellular
homeostasis suggests that their differential expression could contribute to
the toxicity associated with AFB1 exposure.
相似文献
8.
9.
Efficient activation of aflatoxin B1 by cytochrome P450 2A13, an enzyme predominantly expressed in human respiratory tract 总被引:3,自引:0,他引:3
He XY Tang L Wang SL Cai QS Wang JS Hong JY 《International journal of cancer. Journal international du cancer》2006,118(11):2665-2671
The worldwide human exposure to aflatoxin B1 (AFB1), particularly in developing countries, remains to be a serious public health concern. Although AFB1 is best known as a hepatocarcinogen, epidemiological studies have shown a positive association between human lung cancer occurrence and inhalation exposure to AFB1. Cytochrome P450 (CYP)-catalyzed metabolic activation is required for AFB1 to exert its carcinogenicity. Previous studies have identified CYP1A2 and CYP3A4 as the major enzymes for AFB1 activation in human liver. However, the key CYP enzymes in human lung that can efficiently activate AFB1 in situ are unknown. In the present study, we demonstrate that CYP2A13, an enzyme predominantly expressed in human respiratory tract, has a significant activity in metabolizing AFB1 to its carcinogenic/toxic AFB1-8,9-epoxide and AFM1-8,9-epoxide at both low (15 microM) and high (150 microM) substrate concentrations. Under the same conditions, there was no detectable AFB1 epoxide formation by CYP2A6, which was also reported to be involved in the metabolic activation of AFB1. Consistent with the activity data, there was an approximately 800-fold difference in LC50 values of AFB1 (48-hr treatment) between Chinese hamster ovary (CHO) cells expressing CYP2A13 and CYP2A6 (50 nM versus 39 microM). We further demonstrate that amino acid residues Ala117 and His372 in CYP2A13 protein are important for AFB1 epoxidation and its related cytotoxicity. Our results suggest that CYP2A13-catalyzed metabolic activation in situ may play a critical role in human lung carcinogenesis related to inhalation exposure to AFB1. 相似文献
10.
The formation of covalent aflatoxin-DNA adducts has been studied in embryo and yearling stages of the rainbow trout (Salmo gairdneri). A linear relationship was found between the amount of aflatoxin B1 (AFB1) absorbed into 21-day-old eggs and the level of covalent modification of embryo DNA after exposure to 0.25 to 0.5 p.p.m. aqueous solutions of AFB1 for 1 h; higher concentrations resulted in absorption of a greater proportion of AFB1. The principal covalent product, identified after acid and enzymatic hydrolysis of isolated embryo DNA, was chromatographically identical to 2,3-dihydro-2-(N7-guanyl)-3-hydroxy aflatoxin B1. Additional AFB1 derivatives which were present are believed to be formed by chemical transformation of this product in DNA producing an aflatoxin-formamidopyrimidine adduct and the metabolic activation of other aflatoxin metabolites, such as aflatoxin M1 and aflatoxin P1. Although the eggs were exposed to AFB1 for a short time, covalent modification of DNA was evident over an extended period. The highest level of covalent products was present at approximately 24 h after exposure to 0.5 p.p.m. AFB1. Ninety-six hours later, this level had decreased slightly; however, the distribution of covalent adducts had changed: formamidopyrimidine adducts now represented up to 50% of the hydrolyzed aflatoxin derivatives. A similar pattern of covalent aflatoxin derivatives was found in the liver DNA of yearling trout 10 h after the administration of 0.3 mg/kg AFB1. 相似文献
11.
McMahon M Itoh K Yamamoto M Chanas SA Henderson CJ McLellan LI Wolf CR Cavin C Hayes JD 《Cancer research》2001,61(8):3299-3307
12.
T W Kensler P A Egner N E Davidson B D Roebuck A Pikul J D Groopman 《Cancer research》1986,46(8):3924-3931
The effects of dietary administration of ethoxyquin (EQ) on aflatoxin B1 (AFB1) metabolism, DNA adduct formation and removal, and hepatic tumorigenesis were examined in male Fischer rats. Rats were fed a semipurified diet containing 0.4% EQ for 1 wk, gavaged with 250 micrograms of AFB1 per kg 5 times a wk during the next 2 wk, and, finally, restored to the control diet 1 wk after cessation of dosing. At 4 mo, focal areas of hepatocellular alteration were identified and quantitated by staining sections of liver for gamma-glutamyl transpeptidase. Treatment with EQ reduced by greater than 95% both area and volume of liver occupied by gamma-glutamyl transpeptidase-positive foci. Utilizing the same multiple dosing protocol, patterns of covalent modifications of DNA by AFB1 were determined. EQ produced a dramatic reduction in the binding of AFB1 to hepatic DNA: 18-fold initially and 3-fold at the end of the dosing period. Although binding was detectable at 3 and 4 mo postdosing, no effect of EQ was observed, suggesting that these persistent adducts are not of primary relevance to AFB1 carcinogenesis. Analysis of nucleic acid bases by high-performance liquid chromatography revealed no qualitative differences in adduct species between treatment groups. The inhibitory effect of EQ on AFB1 binding to DNA and tumorigenesis appears related to induction of detoxication enzymes. Rats fed 0.4% EQ for 7 days showed a 5-fold increase in hepatic cytosolic glutathione S-transferase (GST)-specific activities. Multiple molecular forms of GST were induced, and concomitant elevations in messenger RNA levels coding for the synthesis of GST subunits were observed. Correspondingly, biliary elimination of AFB1-glutathione conjugate was increased 4.5-fold in animals on the EQ diet during the first 2 h following p.o. administration of 250 micrograms of AFB1 per kg. Thus, induction by EQ of enzymes important to AFB1 detoxication, such as GST, can lead to enhanced carcinogen elimination, as well as reductions of AFB1-DNA adduct formation and subsequent expression of preneoplastic lesions, and, ultimately, neoplasia. 相似文献
13.
Modulation of aflatoxin-B1 hepatocarcinogenesis in trout by dehydroepiandrosterone: initiation/post-initiation and latency effects 总被引:1,自引:0,他引:1
Previously, we demonstrated that dehydroepiandrosterone (DHEA) enhances
aflatoxin B1 (AFB1) hepatocarcinogenesis in trout when administered
following AFB1 exposure. This paper examines the effect of DHEA on tumor
latency and the comparative potency for DHEA to modulate AFB1
carcinogenesis when administered prior to and concurrent with AFB1 compared
with a post-initiation exposure. Trout were initiated by a 30 min water
bath exposure to 10 p.p.b. AFB1. At 3 months post-initiation, animals were
started on either control diet or a diet containing 444 p.p.m.
dehydroepiandrosterone (DHEA). Fifty trout per treatment were sampled prior
to the start of experimental diets, and then at monthly intervals for the
next 7 months and examined for the presence of tumors. Tumors were not
detected in initiated controls until 7 months after initiation. In
initiated trout fed DHEA, the first tumor was detected 5 months after
initiation (after just 2 months of dietary DHEA). At 6 months
post-initiation, 20% of the AFB1-initiated trout fed DHEA had tumors, while
no tumors were visible in either AFB1-initiated controls or noninitiated
trout fed DHEA. A second experiment was designed to determine if the
enhancing effect of DHEA on AFB1 carcinogenesis is dependent on the time of
DHEA administration relative to the time of AFB1 exposure, and if DHEA
could be chemopreventive if administered prior to and concurrent with AFB1.
Trout were fed one of two levels of DHEA (888 or 1776 p.p.m.) either prior
to and during a 4- week initiation period of dietary AFB1 administration,
or for 8 weeks following initiation with AFB1. At 9 months after initiation
the livers were examined for tumors. Neither exposure protocol provided
protection towards AFB1 hepatocarcinogenesis. The strongest enhancement
occurred when DHEA was fed during the post-initiation period. Levels of p53
and p34cdc2 were decreased by DHEA treatment, indicating that DHEA may act
through alterations in cell-cycle control.
相似文献
14.
Chemopreventive Potential of Neem Flowers on Carcinogen-induced Rat Mammary and Liver Carcinogenesis
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《Asian Pacific journal of cancer prevention》2002,3(3):231-238
We have previously reported that dietary neem flowers (Azadirachta indica A. Juss var. siamensis Valeton) caused a marked increase in glutathione S-transferase (GST) activity in the liver, while resulting in a significant reduction in the activities of some hepatic P450-dependent monooxygenases. These results strongly indicate that neem flowers may have chemopreventive potential. In the present study, we examined the inhibitory effects of neem flowers on 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced mammary gland carcinogenesis in female Sprague Dawley rats and on aflatoxin B 1 (AFB1)-induced hepatocarcinogenesis in male Wistar rats. Young animals were fed with AIN-76 purified diets containing either 10-12.5% ground freeze-dried neem flowers for 1 week prior to, during, and for 1 week after the administration of each carcinogen. Interestingly, it was found that neem flowers resulted in a marked reduction of the incidence of mammary gland (about 35.2%) and liver tumors (61.7% and 80.1% for benign and malignant tumors, respectively). Furthermore, the multiplicity of tumors per rats was also lower in the neem flower groups, i.e. those for mammary gland tumors and benign and malignant liver tumors were reduced to 44.0%, 87.9% and 88.9%, respectively. These results clearly demonstrated that neem flowers contain some chemopreventive agents capable of inhibiting AFB1 and DMBA induced liver and mammary gland carcinogenesis in rats. 相似文献
15.
Glutathione (GSH) conjugation of microsome-mediated and synthetic aflatoxin B1 (AFB1)-epoxide and styrene oxide has been investigated with purified GSH S-transferases (GSTs) from rats. Both styrene oxide and AFB1-epoxide were conjugated preferentially by millimicrons GSTs 3-3, 3-4 and 4-4 as compared to alpha GSTs 1-1, 1-2 and 2-2. The highest catalytic activity with styrene oxide conjugation was associated with GST 4-4. The highest catalytic activity with microsome-mediated AFB1-epoxide conjugation was observed with GST 3-3 whereas with the synthetic AFB1-epoxide conjugation was seen with GST 4-4. The catalytic activity of pi GST 7-7 was intermediate to millimicrons and alpha GSTs. It is suggested that GST 3-3 may play an important role in inactivation of AFB1-epoxide generated in vivo in the rat. 相似文献
16.
Oganesian A Hendricks JD Pereira CB Orner GA Bailey GS Williams DE 《Carcinogenesis》1999,20(3):453-458
Indole-3-carbinol (I3C), a metabolite of glucobrassicin found in cruciferous vegetables, is documented as acting as a modulator of carcinogenesis and, depending on timing and dose of administration, it may promote hepatocarcinogenesis in some animal models. In this study we demonstrate that, when given post-initiation, dietary I3C promotes aflatoxin B1 (AFB1)-induced hepatocarcinogenesis in the rainbow trout model at levels as low as 500 p.p.m. Trout embryos (approximately 9000) were initiated with 0, 25, 50, 100, 175 or 250 p.p.b. AFB1 by a 30 min immersion. Experimental diets containing 0, 250, 500, 750, 1000 or 1250 p.p.m. I3C were administered starting at 3 months and fish were sampled for liver tumors at 11-13 months. Promotion at the level of tumor incidence was statistically significant for all dietary levels, except 250 p.p.m. Relative potency for promotion markedly increased at dietary levels >750 p.p.m. We propose that more than one mechanism could be involved in promotion and that both estrogenic and Ah receptor-mediated pathways could be active. The estrogenicity of I3C, measured as its ability to induce vitellogenin (an estrogen biomarker in oviparous vertebrates) was evident at the lowest dietary level (250 p.p.m.), whereas CYPIA (a P450 isozyme induced through the Ah receptor pathway) was not induced until dietary levels of 1000 p.p.m. Therefore, at lower dietary levels, promotion by I3C in this model could be explained by estrogenic activities of I3C acid derivatives, as it is known that estrogens promote hepatocarcinogenesis in trout. Much stronger promotion was observed at high dietary I3C levels (1000 and 1250 p.p.m.), at which levels both CYP1A and vitellogenin were induced. 相似文献
17.
Manson MM; Ball HW; Barrett MC; Clark HL; Judah DJ; Williamson G; Neal GE 《Carcinogenesis》1997,18(9):1729-1738
A range of potential chemoprotective agents, most of them natural dietary
constituents, has been examined for ability to modulate both phase I
(cytochrome P450 1A1, 1A2, 2B1/2, 2C11, 2E1, 3A, 4A) and phase II drug
metabolizing enzymes (glutathione S-transferases, in particular subunits
Yc2 and P, aflatoxin B1-aldehyde reductase and quinone reductase) in rat
liver. In addition to assays of total enzyme activity and Western blots for
individual isozymes, the ability of microsomes to metabolize aflatoxin B1,
and of cytosols to conjugate aflatoxin B1 (AFB1)-epoxide to GSH and to
produce AFB1-dialcohol, were measured. Induction of gamma-glutamyl
transpeptidase activity was examined by histochemistry. Differing patterns
of induction were observed, reflecting differences in the control of
expression of the individual enzymes studied. Of the compounds examined,
butylated hydroxytoluene, ethoxyquin, indole-3-carbinol and phenethyl
isothiocyanate were the most potent bifunctional agents (inducing both
phase I and II activities). Oltipraz, while only weakly inducing CYP1A2 and
2B1/2, was a potent inducer of phase II enzymes. Caffeic acid, garlic oil,
sinigrin and propyl gallate all showed some ability to induce phase II
enzymes. 4-Methyl catechol, alpha-tocopherol and red wine decreased certain
phase I enzyme activities, while inducing total GST activity. Butylated
hydroxytoluene, ethoxyquin, garlic oil and indole-3-carbinol induced gamma
glutamyltranspeptidase in periportal hepatocytes. Particularly because of
their ability to induce the detoxifying activities of glutathione
S-transferase Yc2 and aldehyde reductase, butylated hydroxytoluene,
ethoxyquin, indole-3-carbinol, oltipraz, phenethyl isothiocyanate and
sinigrin will be effective blocking agents in rodents, if administered
prior to AFB1. While these studies indicate the relative contributions of
phase I and II metabolism in the overall protective effect in rat, care
should be taken that a similar balance is achieved in man, and that
relevant enzymes or iso forms are induced.
相似文献
18.
Components of garlic have been shown to inhibit a variety of tumors induced by chemical carcinogens. In this study we determined the effects of ajoene and diallyl sulfide (DAS), two organosulfur compounds of garlic, on the metabolism and DNA binding of aflatoxin B1 (AFB1) using rat liver 9000Xg supernatant as the metabolic activation system. Organosoluble and water-soluble metabolites of [3H]AFB1 were isolated by reverse-phase high performance liquid chromatography (HPLC). The effects of ajoene and DAS on glutathione-S-transferase (GST) were determined using 1-chloro-2,4-dinitrobenzene as the substrate. Ajoene and DAS at 100 mg/ml inhibited [3H]AFB1 binding to calf thymus DNA and adduct formation. They decreased the formation of both organosoluble and water-soluble metabolites of [3H]AFB1. Neither compound significantly affected GST activity. These results indicate that ajoene and DAS affected AFB1 metabolism and DNA binding by inhibiting phase I enzymes and may therefore be considered as potential cancer chemopreventive agents. 相似文献
19.
Aflatoxin B1 carcinogenesis and its relation to DNA adduct formation and adduct persistence in sensitive and resistant salmonid fish 总被引:1,自引:0,他引:1
Bailey George S.; Williams David E.; Wilcox Janet S.; Loveland Patricia M.; Coulombe Roger A.; Hendricks Jerry D. 《Carcinogenesis》1988,9(11):1919-1926
Rainbow trout (Salmo gairdneri)and coho salmon (Oncorhyn-chuskisutch) were exposed to aflatoxin B1(AFB1) either by passiveembryo uptake or by dietary treatment after hatching and feedingonset. Trout exposed as embryos to an aqueous solution of 0.5p.p.m. AFB1 for 15 min showed a 62% tumor incidence 12 monthslater, whereas coho salmon exposed to a similar solution for30 min showed only a 9% incidence. The difference between salmonand trout response was even greater by dietary AFB1 treatment.Trout exposed for 4 weeks to 20 p.p.b. dietary AFB1 had a 62%tumor response 12 months later, whereas salmon exposed to 40p.p.b. dietary AFB1 for 4 weeks failed to develop tumors. A5% tumor incidence was observed in salmon 12 months after 3weeks exposure to 5000 p.p.b. dietary AFB1, a lethal dose fortrout. In addition to a lower tumor incidence when comparedto trout, the neoplastic response of salmon to AFB1 is to producebenign hepatic adenomas in contrast to the malignant hepatocellularcarcinomas seen in trout. AFB1 metabolism, DNA adduct formation,adduct persistence in vivo and in vitro and cytochrome P-450isozyme composition were compared in livers of trout and salmonto understand the role of metabolism and initiation in thisspecies difference. AFB1-DNA binding was 756 times greaterin trout than salmon liver at various times after AFB1 injection,20 times greater in embryos or in freshly isolated trout hepatocytepreparations after a 1 h incubation with aflatoxin Bl, and 18times greater in trout liver after a three week dietary (80p.p.b.) exposure. The major AFB1-DNA adduct was 8, 9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxinB1 in both species. Persistence of AFB1-DNA adducts in vivoin liver was high compared to mamalian systems, implying thatactive enzymatic removal of bulky DNA adducts is low in bothspecies and probably not a factor in their differential responseto aflatoxin. Species differences in other phase I and phaseII metabolism pathways and in AFB1 elimination were, overall,much less striking than those previously observed for troutfed inhibitors of aflatoxin carcinogenesis. Rates of bileeliminationof AFB1 detoxication products, and total excretion of aflatoxinsinto water after AFB1 exposure, were not significantly differentbetween trout and salmon. Since detoxication differences werenot observed, the species difference in AFB1-DNA binding appearsto reflect less efficient cytochrome P-450 metabolism of aflatoxinto the reactive 8, 9-epoxide in salmon, compared to trout. Insupport of this hypothesis, trout liver microsomes displayeda Km (7.5 µM)for AFB1-DNA adduction in vitro that was7-fold lower than salmon (52 µM). Furthermore, immunoquantitationof various P-450 isozymes suggest that salmon liver microsomeshave much lower amounts of an isozyme immunochemically relatedto trout P-450 LM2 which has previously been shown to be themajor isozyme catalyzing AFB1 8, 9-epoxidation. Other, post-initiationdifferences were not ruled out by these studies and may contributeto the differential response of rainbow trout and coho salmonto AFB1 hepatocarcino-genesis. 相似文献
20.
Modulation of mycotoxin and nitrosamine carcinogenesis by indole-3-carbinol: quantitative analysis of inhibition versus promotion 总被引:3,自引:0,他引:3
G S Bailey R H Dashwood A T Fong D E Williams R A Scanlan J D Hendricks 《IARC scientific publications》1991,(105):275-280
The value of chemopreventive agents for reducing human response to mycotoxins and N-nitrosamines remains uncertain, especially since many such agents also can act as tumour promoters. Indole-3-carbinol (I3C) from cruciferous vegetables can inhibit DNA adduction and hepatocarcinogenesis induced by aflatoxin B1 (AFB1) or N-nitroso-diethylamine in trout if given before and with the carcinogen but promotes carcinogenesis when given after initiation. Similar results have been obtained with I3C and AFB1 in rats. In detailed studies using 10,000 trout, inhibition of AFB1 carcinogenesis was found to be saturable at high doses of I3C, approximately proportional to dose of I3C through the range of human intake and, within this range, quantitatively predicted by I3C-mediated reduction of AFB1-DNA adduction in liver. In a second study, post-initiation promotion of AFB1 carcinogenesis was approximately proportional to I3C dose, increased with duration of exposure, decreased with delayed onset of exposure, and reduced but still significant when I3C was given on alternate months or weeks or twice per week only. Hence, promotion by this common component of cruciferous vegetables required prolonged exposure but not necessarily on a daily basis. 相似文献