UMLS:C0596263 - FACTA Search

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Query: UMLS:C0596263 (carcinogenesis)
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A major target tissue for carcinogenesis from the cooked-food carcinogen 2-amino-l-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rodents is the colon, yet the role of colon metabolism on the carcinogenicity of PhIP is not clearly understood. The mutagenic potency of PhIP is highly dependent upon cytochrome P450 N-hydroxylation. In the present study, the ability of rat colon tissue to activate PhIP to a mutagen was investigated in Salmonella typhimurium (strains TA98 and YGI024) and rat colon tissue slices. In the Ames/Salmonella assay, using rat colon S9 as the activating system, no mutations were evident from bacteria exposed to PhIP at any concentration tested. However, mutations were observed when bacteria were exposed to 2-aminoanthracene (2AA) and colon S9, indicating sufficient P450 activity in the S9 to activate 2AA but not PhIP. In rat colon slice preparations, the sulfotransferase and acetyltransferase inhibitors pentachlorophenol (PCP) and 2,6-dichloro-4-nitrophenol (DCNP) were used to modulate DNA adduct and metabolite formation. Incubations of 3-methylcholanthrene-induced colon slices dosed with 50 microMolar [(3)H]PhIP produced no detectable metabolites. However, incubations of uninduced slices exposed to 10 microMolar of the reactive intermediate, [(3)H]2-(hydroxyamino)-l-methyl-6-phenylimidazo[4,5-b]pyridine (N-hydroxy-PhIP), produced a single detectable metabolite, a glucuronide conjugate of N-hydroxy-PhIP. This metabolite decreased when PCP or DCNP was added to the incubation medium. DNA adducts were detected in colon slices exposed to N-hydroxy-PhIP at approximately 33 adducts/10(7) nucleotides. Interestingly, when PCP was added to the incubation mixture, an increase in DNA adduct levels was detected, whereas DCNP produced a decrease in adducts. Because these inhibitors are thought to have similar mechanisms with regard to sulfotransferase inhibition, the inverse relationship in DNA adduct levels due to PCP or DCNP treatment is at present unexplainable. The formation of DNA adducts and metabolites from colon slices exposed to N-hydroxy-PhIP but not PhIP implies that there is insufficient P450 activity in the rat colon to activate PhIP to hydroxylated metabolites, suggesting that the rat colon is a site of Phase II metabolism for PhIP and that the liver is the primary source for hydroxylation.
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PMID:The capability of rat colon tissue slices to metabolize the cooked-food carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. 865 96

Sulfotransferases constitute a superfamily of related enzymes that play critical roles in the regulation of steroid hormone action, neurotransmitter function, detoxification, and carcinogenesis. Understanding the functional relationships among these enzymes has so far been difficult due to their overlapping substrate specificities. To help clarify these relationships, we conducted a thorough and comprehensive molecular phylogenetic analysis of 25 different mammalian sulfotransferase cDNA and gene (St) sequences using maximum parsimony and distance matrix methods. This analysis suggested five distinct gene families: an alcohol/androgen/hydroxysteroid/dehydroepiandrosterone (Std) family, an aryl/minoxidil/phenol (Stp) family, an estrone/estrogen (Ste) family, a thyroid hormone family (St1b1), and a family (St1c1) defined so far only on the basis of its specificity for the carcinogen N-hydroxy-2-acetylaminofluorene. New insights obtained through this study include (1) a bootstrap analysis supporting the reliability of family subgroupings, (2) identification of an insertion that appears to be characteristic of the St1b1 and Stlc1 families, (3) identification of sequences likely to represent paralogs of multigene families, and (4) identification of species likely to contain, or not contain, orthologous multigene families and thus their specialized functions.
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PMID:Structural relationships among members of the mammalian sulfotransferase gene family. 868 69

The antiandrogenic and gestagenic steroid cyproterone acetate (CPA) has been widely used in human therapy. There is currently a debate about the safety of CPA, since it proved to be genotoxic in rat liver and human hepatocytes [I. Neumann et al., Carcinogenesis (Lond.), 13: 373-378, 1992, J. Topinka et al., Carcinogenesis (Lond.), 14: 423-427, 1993, L. R. Schwarz et al., Biological Reactive Intermediates: V. Basic Mechanistic Research in Toxicology and Human Risk Assessment. pp. 243-251, 1996; A. Martelli et al., Carcinogenesis (Lond.), 16: 1265-1269, 1995]. Little is known about the metabolic pathways of activation of CPA to genotoxic metabolites. Using rat hepatocytes and subcellular fractions of female rat liver, we have examined whether sulfoconjugation plays an essential role in the activation of CPA to DNA-binding metabolites which are detectable with 32P-postlabeling. Incubation of hepatocyte cultures with 30 microM CPA for 6 h caused the formation of several DNA adducts; the total adduct level amounted to about 12,400 adducts/10(9) nucleotides. When the cells were incubated in sulfate-free medium to prevent the synthesis of the cosubstrate of sulfonation, 3'-phosphoadenosine-5'-phosphosulfate (PAPS), formation of all CPA-DNA adducts was greatly reduced, amounting to only 5% of that determined in the presence of sulfate (810 microM). Activation of CPA is likely to be catalyzed by hydroxysteroid sulfotransferase(s), because the specific substrate dehydroepiandrosterone almost completely inhibited DNA-binding of CPA. Our assumption that sulfonation plays a decisive role in the bioactivation of CPA is further supported by the results obtained with an in vitro system consisting of calf thymus DNA, various subcellular liver fractions, and the cofactor PAPS, NADPH, or NADH. Significant DNA binding only occurred when cytosol and both PAPS and the reduced pyridine nucleotides were present. The DNA adduct spot obtained was chromatographically identical to the adduct spot A detected in isolated liver cells, suggesting that the CPA-DNA adduct formed in vivo and in vitro is identical. Cytosol is known to contain not only sulfotransferases but also reductases. Thus, the requirement for NADPH or NADH suggests that in addition to sulfotransferase(s), reductases are involved in the activation of CPA. We propose that bioactivation of CPA involves reduction of the keto group at C-3 followed by sulfonation of the hydroxysteroid. The resulting sulfoconjugate is most likely unstable and supposed to generate a reactive carbonium ion.
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PMID:Steroidal drug cyproterone acetate is activated to DNA-binding metabolites by sulfonation. 881 32

N-Hydroxy-N-2-fluorenylacetamide (N-OH-2-FAA) and its benzamide analogue N-OH-2-FBA are mammary gland carcinogens in the female Sprague-Dawley rat. Ovariectomy inhibits tumorigenicity of topically applied N-OH-2-FAA suggesting modulation of carcinogen-activating enzymes in the gland. This study concerned the activation of N-OH-2-FAA and N-OH-2-FBA by the mammary gland and liver, a chief site of metabolism, from 50-day-old female rats and effects on the activation of ovariectomy performed at 22 days of age. The levels of N-debenzolyation of N-OH-2-FBA to N-hydroxy-N-2-fluorenamine (N-OH-2-FA), catalyzed by microsomal carboxylesterases in mammary gland and liver were similar and increased 1.5- and 1.7-fold, respectively, by ovariectomy. N-Debenzoylating activity in cytosols of both tissues appeared to be partially of microsomal origin. Mammary gland cytosol contained N-, O- and N,O-acyltransferase activities at levels 40-50% those of liver. N-Acyltransferase activity was determined via acetyl coenzyme A (AcCoA)-dependent acetylation of 2-FA and a new assay, N-OH-2-FAA-dependent acetylation of 9-oxo-2-FA. The latter activity was decreased in mammary gland by ovariectomy. Microsomal N-acyltransferase activities were <36% those of cytosols. AcCoA-dependent binding of N-OH-2-[ring-[3H]FBA to DNA, catalyzed by cytosol, was consistent with a two-step activation of N-OH-2-FBA involving esterase-catalyzed N-debenzoylation to N-OH-2-FA and its O-acyltransferase-catalyzed acetylation to the electrophilic N-acetoxy-2-FA. O-Acetyltransfer by mammary gland appeared to be rate-limiting since ovariectomy-dependent increases in N-debenzoylation did not increase binding with S9 fraction. Little or no sulfotransferase-catalyzed binding of N-OH-2-[ring-3H]FBA-derived N-OH-2-[ring-3H]FA was detected in the liver or mammary gland cytosol, respectively. The level of binding of N-OH-2-[ring-3H]FAA to DNA catalyzed by cytosolic N,O-acyltransferase was decreased approximately 23% in mammary gland and increased 1.2-fold in liver by ovariectomy. 32P-Postlabeling analyses indicated a single adduct N-(deoxyguanosin-8-yl)-2-fluorenamine in DNA of both tissues 24 h after one intraperitoneal injection of N-OH-2-FBA or N-OH-2-FAA. Respective levels were 3.6- and 5.5-fold greater in liver than mammary gland. After ovariectomy, the adduct levels from N-OH-2-FBA increased 1.8-fold in mammary gland and from N-OH-2-FAA decreased approximately 50% in both tissues. Thus, the ovariectomy-dependent changes in levels of enzymes activating N-OH-2-FBA and N-OH-2-FAA were consistent with in vivo DNA adduct levels in the target mammary gland, but not in the liver.
Carcinogenesis 1996 Nov
PMID:Effect of ovariectomy on the in vitro and in vivo activation of carcinogenic N-2-fluorenylhydroxamic acids by rat mammary gland and liver. 896 56

The sulfation of primary N-hydroxy arylamines is a critical intermediate step in the bioactivation of many carcinogenic arylamines, arylamides and nitroaromatics. However, the study of this reaction in vitro is often complicated by the chemical instability of these molecules. We have examined the stability of two highly purified N-hydroxy arylamines, N-hydroxyaniline and N-hydroxy-2-aminofluorene, under different oxidative reaction conditions pertinent to the assay of sulfotransferases. Furthermore, these compounds, as well as the products of their oxidative degradation, were examined for their interactions with homogeneous aryl sulfotransferase (AST) IV. Under reaction conditions where oxidative degradation of the N-hydroxy arylamines occurred, N-hydroxyaniline and N-hydroxy-2-aminofluorene produced time-dependent and irreversible inhibition of AST IV. While this inhibition was not dependent upon the presence of 3'-phosphoadenosine 5'-phosphosulfate in the reaction mixture, analysis of the N-hydroxy arylamines by UV spectroscopy showed that the inhibition of AST IV did require non-enzymatic oxidation of the N-hydroxy arylamine. Under reaction conditions that prevented the oxidative degradation of N-hydroxyaniline, this N-hydroxy arylamine was a substrate for AST IV. Likewise, under similar conditions, 4-chloro-N-hydroxyaniline was also a substrate for the enzyme. In contrast, no AST IV catalyzed sulfation of N-hydroxy-2-aminofluorene was detected under conditions that prevented the oxidation of N-hydroxy-2-aminofluorene. Adequate protection of these N-hydroxy arylamines from oxidative degradation required the addition of L-ascorbic acid to reaction mixtures that had also been degassed and purged with argon. The irreversible inhibition of AST IV exhibited by these N-hydroxy arylamines, even in reaction mixtures where attempts were made to limit oxidative degradation by degassing and purging with argon, emphasized the importance of completely preventing such degradation when utilizing in vitro assays to assess the potential for an N-hydroxy arylamine to serve as a substrate for a specific sulfotransferase.
Carcinogenesis 1997 Apr
PMID:Oxidation-dependent inactivation of aryl sulfotransferase IV by primary N-hydroxy arylamines during in vitro assays. 911 Dec 23

Epidemiologic studies have suggested that aromatic amines (and nitroaromatic hydrocarbons) may be carcinogenic for human pancreas. Pancreatic tissues from 29 organ donors (13 smokers, 16 non-smokers) were examined for their ability to metabolize aromatic amines and other carcinogens. Microsomes showed no activity for cytochrome P450 (P450) 1A2-dependent N-oxidation of 4-aminobiphenyl (ABP) or for the following activities (and associated P450s): aminopyrine N-demethylation and ethylmorphine N-demethylation (P450 3A4); ethoxyresorufin O-deethylation (P450 1A1) and pentoxyresorufin O-dealkylation (P450 2B6); p-nitrophenol hydroxylation and N-nitrosodimethyl-amine N-demethylation (P450 2E1); lauric acid omega-hydroxylation (P450 4A1); and 4-(methylnitrosamino)-1-(3-pyridyl-1-butanol) (NNAL) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) alpha-oxidation (P450 1A2, 2A6, 2D6). Antibodies were used to examine microsomal levels of P450 1A2, 2A6, 2C8/9/18/19, 2E1, 2D6, and 3A3/4/5/7 and epoxide hydrolase. Immunoblots detected only epoxide hydrolase at low levels; P450 levels were <1% of liver. Microsomal benzidine/prostaglandin hydroperoxidation activity was low. In pancreatic cytosols and microsomes, 4-nitrobiphenyl reductase activities were present at levels comparable to human liver. The O-acetyltransferase activity (AcCoA-dependent DNA-binding of [3H]N-hydroxy-ABP) of pancreatic cytosols was high, about twothirds the levels measured in human colon. Cytosols showed high activity for N-acetylation of p-aminobenzoic acid, but not of sulfamethazine, indicating that acetyltransferase-1 (NAT1) is predominantly expressed in this tissue. Cytosolic sulfotransferase was detected at low levels. Using 32P-post-labeling enhanced by butanol extraction, putative arylamine-DNA adducts were detected in most samples. Moreover, in eight of 29 DNA samples, a major adduct was observed that was chromatographically identical to the predominant ABP-DNA adduct, N-(deoxyguanosin-8-yl)-ABP. These results are consistent with a hypothesis that aromatic amines and nitroaromatic hydrocarbons may be involved in the etiology of human pancreatic cancer.
Carcinogenesis 1997 May
PMID:Metabolic activation of aromatic amines by human pancreas. 916

Down regulation of aryl sulfotransferase IV (AST IV) in promotion/progression of liver carcinogenesis by N-2-fluorenylacetamide (2-FAA) has been established. This study examined whether the C-9 oxidized metabolites of 2-FAA, which have recently been shown to promote diethylnitrosamine (DEN)-initiated liver carcinogenesis in male Sprague-Dawley rats, effect the above change. Hence, in DEN-initiated rats, the effects of promoting regimens of 9-OH-2-FAA or 9-oxo-2-FAA, 15 oral doses at 50 and 100 mumol/kg of body weight, were compared to those of 2-FAA at 50 mumol/kg of body weight and of the vehicle on the activity of N-hydroxy(OH)-2-FAA sulfotransferase (ST), an isozyme of AST IV and AST IV expression and distribution. Relative to the vehicle, treatment with the fluorenyl compounds led to decreased levels in hepatic N-OH-2-FAA ST activity and development of hepatic nodules and tumors which had still lower levels of the ST activity than the respective remnant livers. At approximately 8 months after treatment with the C-9-oxidized compounds at doses twice that of 2-FAA, the extents of decreases in the hepatic N-OH-2-FAA ST activity and cytosolic AST IV protein in tumors were comparable to those with 2-FAA. Immunocytochemical analysis showed close association of AST IV deficiency with neoplastic liver lesions. In comparison to N-OH-2-FAA, 9-OH-2-FAA had only low and 9-oxo-2-FAA lacked sulfate acceptor activity in the presence of male rat liver cytosol or AST IV. At 3.3-fold greater concentration than N-OH-2-FAA, 9-oxo-2-FAA inhibited (27%) the sulfate acceptor activity of N-OH-2-FAA in the presence of AST IV, which suggested interference by 9-oxo-2-FAA at the active site. Although the C-9-oxidized compounds do not appear to be substrates for N-OH-2-FAA ST, their ability to cause a decrease in N-OH-2-FAA ST activity and protein similar to that of 2-FAA supports their role in hepatocarcinogenesis. Whereas 9-OH-2-FAA had a 3.9-fold greater sulfate acceptor activity in the presence of female than male rat liver cytosol and inhibited dehydroepiandrosterone ST activity of female rat liver, N-OH-2-FAA and 9-oxo-2-FAA inhibited estrone ST activity of male rat liver, suggesting that the C-9-oxidized compounds as well as N-OH-2-FAA are substrates for STs other than AST IV.
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PMID:Aryl sulfotransferase IV deficiency in rat liver carcinogenesis initiated with diethylnitrosamine and promoted with N-2-fluorenylacetamide or its C-9-oxidized metabolites. 931 85

Carcinogenic arylamines such as N-hydroxy-2-acetylaminofluorene (N-OH-AAF) are metabolically activated by mammalian sulfotransferases to form N-hydroxyarylamine O-sulfates. We previously showed that rat ST1C1 efficiently mediate these activations. These reactions occur in liver cytosols of humans as well as rats. However, the enzyme responsible for N-OH-AAF activation has not been identified in humans. In the present study, a human cDNA (ST1C2) encoding a sulfotransferase showing a high similarity with ST1C1, has been isolated from a human fetal liver cDNA library and expressed using a bacterial expression system. A clear difference was observed in the pH optima for p-nitrophenol sulfation between ST1C2 and ST1C1 expressed in Escherichia coli. In addition, ST1C2 did not mediate 3'-phosphoadenosine-5'-phosphosulfate-dependent DNA binding of N-OH-AAF. These results suggest that human ST1C2 has a clear different substrate specificity, in spite of the structural similarity, with rat ST1C1.
Carcinogenesis 1998 May
PMID:Molecular characterization of ST1C1-related human sulfotransferase. 963 88

Methyl-hydroxylated metabolites of the potent carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA), namely, 7-hydroxymethyl-12-methylbenz[a]anthracene (7-OH-DMBA), 7-methyl-12-hydroxymethylbenz[a]anthracene (12-OH-DMBA) and 7,12-dihydroxymethylbenz[a]anthracene (7,12-diOH-DMBA), were examined as substrates for sulfotransferase bioactivation in different human tissue cytosols. Hepatic cytosols, which were able to catalyze the 3'-phosphoadenosine 5'-phosphosulfate (PAPS)-dependent DNA binding of 7-OH-DMBA, 12-OH-DMBA and 7,12-diOH-DMBA, were highly sensitive to inhibition by dehydroepiandrosterone (DHEA), a specific substrate for human DHEA-steroid sulfotransferase (IC50 = 5 microM). By comparison, 2,6-dichloro-4-nitrophenol, a potent inhibitor of the thermostable (TS)-phenol and estrogen sulfotransferases, did not have an appreciable inhibitory effect. Neither p-nitrophenol, a high affinity substrate for human TS-phenol and estrogen sulfotransferases, nor dopamine, a specific substrate for the thermolabile (TL)-phenol sulfotransferase, significantly inhibited the DNA binding of 12-OH-DMBA catalyzed by hepatic cytosols. Inter-subject variation (n = 12) of the PAPS-dependent DNA binding of 12-OH- and 7,12-diOH-DMBAs also correlated well with DHEA-sulfotransferase activity (r = 0.90; P < 0.00001 and r = 0.92; P < 0.00001, respectively). This sulfation-dependent metabolic activation was not detected in cytosols from human colon, pancreas, larynx or mammary gland. Both TS- and TL-phenol sulfotransferases were active in human liver and colon but only liver contained DHEA-sulfotransferase activity. These results indicate that the sulfotransferase-mediated activation of the methyl-hydroxylated DMBAs is predominantly catalyzed by DHEA-steroid sulfotransferase in human liver and that TS- and TL-phenol sulfotransferases and estrogen sulfotransferase are not involved in the catalysis.
Carcinogenesis 1998 Jun
PMID:Metabolic activation of methyl-hydroxylated derivatives of 7,12-dimethylbenz[a]anthracene by human liver dehydroepiandrosterone-steroid sulfotransferase. 966 46

Tamoxifen increases the risk of human endometrial cancer and is a potent carcinogen in rat liver, in which it produces DNA adducts and cytogenetic damage. Nevertheless its prophylactic use against breast cancer in healthy women is under investigation in several large trials. To investigate whether rat hepatocarcinogenicity predicts human hepatocarcinogenicity we used genetically engineered bacterial and mammalian target cells to investigate how alpha-hydroxy-tamoxifen, a major phase I metabolite of tamoxifen, is further metabolised by rat and human phase II enzymes, sulfotransferases, to mutagenic and DNA-adduct-forming species. We expressed rat hydroxysteroid sulfotransferase a, a liver-specific enzyme, and corresponding human sulfotransferase in bacteria (Salmonella typhimurium) and in a mammalian cell line (Chinese hamster V79 cells) and tested alpha-hydroxytamoxifen for DNA adduct formation and mutagenicity in these systems, using unmodified cells as controls. In cells that expressed rat hydroxysteroid sulfotransferase, alpha-hydroxytamoxifen was mutagenic and formed the same pattern of DNA adducts as that found in the liver of tamoxifen-treated rats. Alpha-hydroxytamoxifen was not activated, or was at least 20 times less active in cells expressing human hydroxysteroid sulfotransferase. All the other six known human xenobiotic-metabolising sulfotransferases were also expressed in S. typhimurium. None activated alpha-hydroxytamoxifen to a mutagen. These results suggest that the risk of DNA adduct formation, and cancer, in the human liver is low and explain why tamoxifen is a powerful carcinogen to the rat liver, and why standard short-term tests fail to detect its mutagenicity.
Carcinogenesis 1998 Oct
PMID:Rat, but not human, sulfotransferase activates a tamoxifen metabolite to produce DNA adducts and gene mutations in bacteria and mammalian cells in culture. 980 49

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