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

Brief exposure of rats to hepatocarcinogenic agents causes a rapid elevation in hepatic microsomal epoxide hydrolase (EH) activity. Previous studies have demonstrated that animals which are resistant to the hepatocarcinogenic effects of 2-acetylaminofluorene (AAF) are also resistant to EH induction by this compound. The studies described here were designed to examine the role of several individual metabolic pathways on the induction of EH by AAF. EH was increased 4-fold in male Fischer 344 (F-344) or Sprague-Dawley (SD) rats treated with AAF; in female rats, deficient in N-hydroxylase and sulfotransferase activities, the activity was increased only 2-fold. Pretreatment of male F-344 rats with inducers of cytochrome P-448 activity caused a reduction in the EH response to AAF, probably due to a greater increase in ring-hydroxylation than N-hydroxylation of the AAF. Although AAF elicited only a small EH elevation in female F-344 rats, N-hydroxy-2-acetylaminofluorene (N-OH-AAF) caused a large increase in these animals. The N-OH-AAF-induced increase was partially blocked by pretreatment with pentachlorophenol, an inhibitor of sulfotransferase activity, in both male and female F-344s. In female SD rats, possessing minimal sulfotransferase activity, N-OH-AAF treatment caused only a slight elevation of EH activity. Pretreatment of male F-344 rats with inhibitors of deacetylase activity had no effect on N-OH-AAF-dependent EH induction. These observations are consistent with the suggestion that formation of the sulfate conjugate of N-OH-AAF is necessary for elevation of EH by this compound.
Carcinogenesis 1985 Jul
PMID:Elevation of hepatic microsomal epoxide hydrolase activity by 2-acetylaminofluorene: role of metabolism. 401 77

The sulfotransferase inhibitors 2,6-dichloro-4-nitrophenol and pentachlorophenol were used to investigate the role of sulfate ester formation during the in vivo bioactivation of 2,4- and 2,6-dinitrotoluene (DNT). Male F-344 rats were administered one of the sulfotransferase inhibitors (40 mu mol/kg i.p.) 45 min prior to oral administration of 28 mg/kg [ring-14C]-2,4-DNT or [3-3H]-2,6-DNT and killed 12 h later. Pentachlorophenol had no significant effect on the urinary excretion of the benzyl glucuronide or benzoic acid metabolites of 2,6-DNT. The sulfotransferase inhibitors decreased the total hepatic macromolecular covalent binding of 2,4-DNT by 33%, and of 2,6-DNT by 69%. Purification of hepatic DNA by hydroxylapatite chromatography indicated covalent binding of 2,4- and 2,6-DNT at levels of 45 and 94 pmol equivalents/mg DNA, respectively. The sulfotransferase inhibitors decreased the binding of the hepatocarcinogen 2,6-DNT to hepatic DNA by greater than 95%. 2,6-Dichloro-4-nitrophenol decreased the binding of 2,4-DNT to DNA by greater than 84% while the decrease due to pentachlorophenol was 33%. These results suggest that sulfation is important in the biotransformation of 2,4- and 2,6-DNT to reactive metabolites which covalently bind to DNA. 3H2O was detected in the urine of rats administered [3-3H]-2,6-DNT. Pentachlorophenol decreased 3H2O formation to the same extent as it decreased the total hepatic macromolecular covalent binding of 2,6-DNT, suggesting that 3H exchange at the 3 position of 2,6-DNT occurs following sulfate ester formation. These results are consistent with a nitrenium-carbonium ion resonance of the sulfate ester-derived reactive intermediate of 2,6-DNT.
Carcinogenesis 1984 Sep
PMID:Hepatic macromolecular covalent binding of the hepatocarcinogen 2,6-dinitrotoluene and its 2,4-isomer in vivo: modulation by the sulfotransferase inhibitors pentachlorophenol and 2,6-dichloro-4-nitrophenol. 659 Jan 36

Benzidine, a human urinary bladder carcinogen, induces hepatic tumors in mice and rats. In this study, [3H]benzidine was administered in drinking water to mice for 1 week, and the covalent binding of the carcinogen to hepatic DNA was then determined. A single carcinogen:DNA adduct was detected which decreased in concentration by approximately 50% at 1 day after treatment and then remained at a nearly constant level for at least 7 days. Injection of radiolabeled benzidine or N-acetyl-benzidine into rats also resulted in a single carcinogen:DNA adduct that was chromatographically identical to that obtained in mouse liver. While administration of benzidine and N-acetylbenzidine resulted in high levels of the adduct in rat hepatic DNA, injection of N,N'-[ring-14C]diacetylbenzidine did not give detectable binding (less than 0.3 residue/mg DNA). The same carcinogen:DNA adduct found in rat and mouse liver was prepared synthetically by: (a) hydrolysis of calf thymus DNA reacted with N-hydroxy-N'-acetylbenzidine at pH 5; and (b) reaction of N-acetoxy-N,N'-diacetylbenzidine with deoxyguanosine and subsequent selective deacetylation of the product with methanolic ammonia. The in vitro and in vivo products were found to have identical high-pressure liquid chromatography retention times and to exhibit similar pH-dependent solvent partitioning characteristics. Mass and nuclear magnetic resonance spectral data on the synthetic products established the structure of the hepatic adduct as N-(deoxyguanosin-8-yl)-N'-acetylbenzidine. The structural isomer, N-(deoxyguanosin-8-yl)-N-acetylbenzidine, was synthesized by treatment of N-(deoxyguanosin-8-yl)-N,N'-diacetylbenzidine (the intermediate in b) with carboxylesterase and was shown to be chromatographically distinct from the in vivo adduct. Similarly, the nonacetylated derivative, N-(deoxyguanosin-8-yl) benzidine, was synthesized by carboxylesterase treatment of N-(deoxyguanosin-8-yl)-N'-acetylbenzidine and was shown not to occur in rat and mouse liver DNA. These data indicate that the metabolic activation of benzidine to an ultimate carcinogen in rats and mice does not involve N-hydroxybenzidine or sulfotransferase-catalyzed activation of N-hydroxy-N,N'-diacetylbenzidine. The remaining pathways for metabolic conversion of benzidine to an ultimate carcinogenic species are discussed in relation to liver and urinary bladder carcinogenesis.
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PMID:Covalent binding of benzidine and N-acetylbenzidine to DNA at the C-8 atom of deoxyguanosine in vivo and in vitro. 708 60

N-Hydroxy-2-acetylaminofluorene (N-OH-AAf) is metabolically converted into reactive N,O-esters which are capable of forming covalent adducts with DNA in rat liver in vivo. The effect of inhibiting one of the proposed pathways, N-O-sulfation, on DNA adduct formation was studied by using a specific sulfotransferase inhibitor, pentachlorophenol. Rats were pretreated with pentachlorophenol and, after 45 min, N-OH-AAF was administered. Four hours after dosing the animals were sacrificed and hepatic DNA was isolated. In DNA from control livers two acetylaminofluorene-and one aminofluorene-substituted deoxyguanosine adducts were found. The acetylaminofluorene derivatives, N-(deoxyguanosin-8-yl)-2--acetylaminofluorene and 3-(deoxyguanosin-N2-yl)-2acetylaminofluorene, accounted for 40% of the total binding in the hydrolyzed DNA. The aminofluorene adduct, N-(deoxyguanosin-8-yl)-2-aminofluorene, accounted for the remainder. In rats that were pretreated with pentacholorphenol, total DNA binding was decreased by 26%. The same three adducts were found, but the acetylaminofluorene adducts were now only 13% of the total, while the aminofluorene adduct accounted for 87%. The absolute amount of aminofluorene adduct was not altered as compared to control rats. These data demonstrate the involvement of N-O-sulfation in carcinogen-DNA binding and indicate that at least 70% of the acetylaminofluorene bound to deoxyguanosine in rat liver DNA, in vivo, is formed through N-O-sulfation of N-OH-AAF.
Carcinogenesis 1981
PMID:Role of sulfation in the formation of DNA adducts from N-hydroxy-2-acetylaminofluorene in rat liver in vivo. Inhibition of N-acetylated aminofluorene adduct formation by pentachlorophenol. 727 22

Some hydroxymethyl-substituted polycyclic aromatic hydrocarbons have been shown to be converted to electrophilic, mutagenic, or tumorigenic sulfuric acid ester metabolites by cytosolic sulfotransferase activity in rodent liver. Likewise, certain types of aromatic compounds with a secondary alcoholic functional group at the benzylic position undergo metabolic activation through sulfonation. Enzymatic oxidation of benzo[a]pyrene produces such secondary alcohols as dihydrodiol and tetraol derivatives as primary metabolites. Sulfo conjugation of the benzylic hydroxy group of each of these metabolites is expected to generate an electrophilic sulfuric acid ester capable of covalently binding to DNA, which may contribute to mutagenesis and carcinogenesis by benzo[a]pyrene. Although the model benzo-ring secondary benzyl alcohol, 7-hydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene, covalently bound to DNA and also exerted mutagenicity in the presence of rodent hepatic cytosols and 3'-phosphoadenosine 5'-phosphosulfate, no such sulfotransferase-dependent activation was observed with dihydrodiol or tetraol derivatives of benzo[a]pyrene. Thus, it seems likely that appearance of the adjacent non-benzylic hydroxy functional group(s) in latter metabolites hinders the benzylic sulfonation in these molecules.
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PMID:Sulfotransferase-mediated activation of 7,8,9,10-tetrahydro-7-ol, 7,8-dihydrodiol, and 7,8,9,10-tetraol derivatives of benzo[a]pyrene. 754 51

The promotional effect of phenobarbital and 1-hydroxymethyl-pyren on enzyme altered lesions in the rat liver were quantified within the framework of two separate multipath/multistage models. The experiment analyzed followed an initiation-promotion protocol in which female Wistar rats were initiated with a single dose of diethylnitrosamine at 0.15 mumol/g body wt followed by a 3 week treatment-free period. A promotor, 1-hydroxymethyl-pyren or phenobarbital was then administered continuously in the diet for 120 days. All animals were sacrificed 3 weeks after treatment and their livers were examined for enzyme histological changes. Focal lesions were classified into three phenotype categories: adenosine triphosphatase altered (ATPase), sulfotransferase altered (ST) and jointly altered lesions (ATPase and ST). Quantitative methods were used to analyze the data, which consisted of the number and sizes of these enzyme-altered lesions. Both multipath/multistage models fitted to the data clearly demonstrate that phenobarbital promotion produced more observable and larger foci than promotion via 1-hydroxymethyl-pyren and that the growth kinetics of the jointly altered lesions were elevated relative to the lesions expressing a single marker. It was not possible with these data to determine if there was a predominant sequence in the formation of jointly altered lesions.
Carcinogenesis 1995 Oct
PMID:Quantitative analysis of multiple phenotype enzyme-altered foci in rat hepatocarcinogenesis experiments: the multipath/multistage model. 758 58

Diethylstilbestrol (DES), a synthetic stilbene estrogen, is a potent development toxin and carcinogen in humans and rodents. A number of 32P-postlabeling studies suggest that genotoxic effects of DES substantially contribute to these biological effects. The mechanisms involved in DES-mediated genotoxicity are not completely understood, however. As reported here, the structural resemblance of tamoxifen to DES led to the hypothesis that DES may be hydroxylated and sulfated at the allylic C2 and/or C5 of the ethyl side chains in analogy to alpha-hydroxylation and sulfation of and DNA adduct formation by tamoxifen. Female ICR mice were administered 500 mumol/kg DES or its dimethyl ether derivative (DiMeDES), either alone or in combination with the sulfotransferase inhibitor pentachlorophenol (PCP) (75 mumol/kg), once daily for 4 days. Liver DNA adducts were measured 24 h after the last dose by dinucleotide/monophosphate 32P-postlabeling. Administration of DES or DiMeDES led to the formation of a unique and novel pattern of several major DNA adducts which were absent in vehicle controls. With minor exceptions the pattern was qualitatively similar for the two compounds, suggesting rapid O-demethylation of DiMeDES to DES in vivo followed by metabolic activation. Adducts formed in vivo did not chromatographically match DES quinone adducts synthesized in vitro. Co-administration of PCP with DES or DiMeDES significantly decreased adduct formation from either compound, by 33-61%. Taken together, these results are consistent with a hitherto unrecognized pathway of metabolic activation and DNA adduct formation by DES involving the putative hydroxylation of the allylic alpha-carbon of the ethyl side chain(s), followed by formation of DNA-reactive sulfuric acid esters. DES is now known to induce DNA damage in vivo by at least four different mechanisms. It is postulated that this multiplicity of mechanisms in itself explains why this drug elicits such a plethora of unique and complex pathophysiological effects in adults and off-spring of different species.
Carcinogenesis 1995 Nov
PMID:Evidence from 32P-postlabeling and the use of pentachlorophenol for a novel metabolic activation pathway of diethylstilbestrol and its dimethyl ether in mouse live: likely alpha-hydroxylation of ethyl group(s) followed by sulfate conjugation. 758 80

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant heterocyclic amine in fried beef, is mammary gland carcinogen in rats. Using the 32P-postlabeling method, PhIP-DNA adduct levels were measured in mammary epithelial cells isolated from female Sprague-Dawley rats given 10 daily doses of PhIP (75 mg/kg, p.o.) according to a protocol previously shown to induce mammary gland cancer. At 24 h, 48 h, 1 week and 5 weeks after the last dose of PhIP, PhIP-DNA adduct levels [relative adduct labeling (RAL) x 10(7), mean +/- SD] were 10.2 +/- 0.7, 7.9 +/- 2.7, 2.2 +/- 0.6 and 0.9 +/- 0.03 respectively. When isolated rat mammary epithelial cells (from untreated rats) were incubated in vitro with N-hydroxy-PhIP (45 microM, 1 h, 37 degrees C), PhIP-DNA adducts were detected in cell DNA (RAL = approximately 97 x 10(7); however, no adducts were detected in cells incubated with PhIP (200 microM, 15 h, 37 degrees C). Incubating cells with pentachlorophenol, an inhibitor of acetyltransferase, or incubating cells at 0-4 degrees C, reduced N-hydroxy-PhIP adduct levels by 45 and 75% respectively, indicating that formation of N-hydroxy-PhIP adducts was largely due to metabolic activation. Further studies showed that rat mammary gland microsomes had little capacity to N-hydroxylate PhIP, as assayed by the mutagenic activation of PhIP in the Ames Salmonella assay. In contrast, N-hydroxy-PhIP was metabolically activated by cytosol-catalyzed PhIP-DNA adduct formation to calf thymus DNA incubated in vitro with N-hydroxy-PhIP (2 microM) in the presence of acetyl CoA. Notably, mammary cytosolic O-acetyltransferase activation of N-hydroxy-IQ or N-hydroxy-MeIQx. All three N-hydroxylamines were activated via cytosolic proline aminoacyl-tRNA synthetase and phosphorylase, although the activities of these enzymes were approximately 100-fold lower than O-acetyltransferase. No mammary cytosolic sulfotransferase activation could be detected with any of the N-hydroxylamines. Our results are consistent with the notion that PhIP-DNA adduct formation and initiation of carcinogenesis in the rat mammary gland may be associated with N-hydroxylation of PhIP outside the mammary gland, transport of the N-hydroxylamine to the mammary gland and subsequent in situ O-acetyltransferase-catalyzed activation of N-hydroxy-PhIP.
Carcinogenesis 1995 Nov
PMID:Possible mechanisms for PhIP-DNA adduct formation in the mammary gland of female Sprague-Dawley rats. 758 92

A comparative study on the metabolic activation and detoxification of the food-borne carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), by human, rat, and mouse hepatic subcellular fractions was conducted to elucidate the mechanism of the interspecies and organ-specific differences in genotoxicity and carcinogenesis. Incubation of PhIP with human, rat, and mouse hepatic microsomes each generated two metabolites, which were identified as N-hydroxy-PhIP and 4'-hydroxy-PhIP. However, the rates of formation of these metabolites differed significantly between species. Human hepatic microsomes had the highest capacity to convert PhIP to the genotoxic metabolite, N-hydroxy-PhIP, with a mean +/- SD value (9.69 +/- 5.15 nmol/mg protein/30 min, N = 3) that was 1.8-fold and 1.4-fold higher than that of rats (5.25 +/- 1.63, N = 3) and mice (6.89 +/- 0.55, N = 3) p < 0.05), respectively. Rodent microsomes were also able to convert PhIP to its nongenotoxic 4'-hydroxy derivative; however, this detoxification pathway was negligible in human hepatic microsomes. The ratio of N-hydroxylation to 4'-hydroxylation was 97:1, 3.3:1, and 1.7:1 for humans, rats, and mice, respectively. The capacities for the further metabolic activation of N-hydroxy-PhIP by cytosolic O-acetyltransferase, sulfotransferase, L-prolyl-tRNA synthetase, and an ATP-dependent kinase(s) were examined using PhIP-DNA binding as a measure of bioactivation. Acetyl coenzyme A-dependent DNA binding of N-hydroxy-PhIP was detected with both human and rodent hepatic cytosols, and showed a significant interspecies difference.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Species differences in the biotransformation of the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine by hepatic microsomes and cytosols from humans, rats, and mice. 760 Sep 22

The effects of dehydroepiandrosterone sulfate (DHAS), a typical hydroxysteroid sulfotransferase (HSTase) inhibitor, and of 3'-phosphoadenosine 5'-phosphate (PAP), a nonspecific sulfation inhibitor on N-nitrosobis(2-oxopropyl)-amine (BOP)-induced initiation were examined in a rapid production model for pancreatic carcinomas in hamsters in order to elucidate the involvement of sulfotransferase in the metabolic activation of beta-oxypropylnitrosamines. While neither low nor high doses of DHAS and PAP exerted any significant influence on the incidence of ductal lesions including carcinomas, the high dose of DHAS (350 mg/kg body wt) and a both low (90 mg/kg) and high (180 mg/kg) doses of PAP reduced the mean numbers of pancreatic ductal adenocarcinomas. The high dose of PAP also reduced the number of all ductal lesions combined. The results thus suggest that metabolic activation with STase is involved in BOP-induced pancreatic ductal carcinogenesis in hamsters, and support the hypothesis that BOP is metabolized to beta-hydroxyalkylnitrosamines followed by activation to proximate sulfuric acid esters by HSTase.
Carcinogenesis 1995 Mar
PMID:Inhibitory effects of sulfation inhibitors on initiation of pancreatic ductal carcinogenesis by N-nitrosobis(2-oxopropyl)amine in hamsters. 769 98


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