Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rat hepatic aryl sulfotransferase IV catalyzes the sulfonation of the hepatocarcinogen, N-hydroxy-2-acetylaminofluorene. The resulting reactive N-O-sulfate ester is believed to be the ultimate carcinogenic species responsible for the induction of hepatic neoplasia. Previous studies have shown that dietary administration of either 2-acetylaminofluorene or N-hydroxy-2-acetylaminofluorene to rats is accompanied by a rapid decline in hepatic aryl sulfotransferase activity in vivo. In the present study, preincubation of purified rat hepatic aryl sulfotransferase IV with N-hydroxy-2-acetylaminofluorene resulted in rapid, time-dependent enzyme inactivation. This in vitro inactivation was not reversed by dialysis or gel filtration. Inclusion of excess nucleophile, methionine, resulted in considerable but not complete protection from inactivation. The inactivation was PAPS dependent and blocked by the sulfotransferase inhibitor, pentachlorophenol. The above observations and the apparent pseudo first-order kinetics observed suggest that the inactivation was in part mechanism based. Mechanism-based inactivation of the aryl sulfotransferases has not been previously reported. Furthermore, the results of the present study indicate that the previously reported in vivo decline in rat hepatic aryl sulfotransferase activity may be attributable in part to enzyme inactivation by its own reactive product.
Carcinogenesis 1990 Sep
PMID:Self-catalyzed irreversible inactivation of rat hepatic aryl sulfotransferase IV by N-hydroxy-2-acetylaminofluorene. 240 Oct 45

Hamsters and rats metabolize [1-14C]N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) and N-nitrosobis(2-oxopropyl)amine (BOP) to yield N-nitrosobis(2-hydroxypropyl)-amine (BHP), glucuronic acid conjugates of HPOP and BHP, the sulfate ester of HPOP and 14C-labeled urea, all of which are excreted, and 14CO2 which is both incorporated in the urea cycle, and exhaled. The extent of metabolism and the ratios of these metabolites does not vary significantly with age or sex of the animal, however, marked species differences are evident in the metabolite composition of urine 6 h following administration of HPOP. Hamsters sulfate HPOP several times more rapidly, and reduce it to BHP more efficiently than rats. In contrast, the rat excretes more unchanged HPOP and its glucuronic acid conjugate than the hamster. Since sulfation and glucuronidation of HPOP may be involved in its activation and detoxication, these reactions were examined in detail in order to elucidate the reason(s) for their distinctively different contributions to its metabolism in rats and hamsters. Conjugation of HPOP with glucuronic acid and sulfate occurs in the livers of both rats and hamsters and is catalyzed by microsomal glucuronyl transferases and cytosolic sulfotransferases, respectively. The levels of glucuronyl transferase activity for conjugating phenolic compounds are comparable in the livers of two species; however, glucuronidation of HPOP is catalyzed by an isozyme the activity of which is three times greater in rat than in the hamster. In contrast to glucuronidation, sulfation of HPOP is catalyzed approximately 10 times faster by hamster than rat liver cytosol. Although rat liver can catalyze sulfation of phenolic compounds very effectively, it has low activity in sulfating aliphatic alcohols and beta-hydroxynitrosamines. Since both aliphatic alcohols and HPOP are sulfated by hamster liver cytosolic preparations and since these reactions are not significantly affected by the classic phenol sulfotransferase inhibitors, it appears that beta-hydroxynitrosamines may be sulfated by the aliphatic (hydroxysteroid) sulfotransferase isozymes. The failure of the rat to extensively sulfate HPOP in vivo may be attributed to the high Km of rat hydroxysteroid sulfotransferases for this compound. Of the four isomers of HPOP, only isomer A, in which the nitroso group is syn to the free keto group, is sulfated in vitro to an appreciable extent. The other three isomers either are not sulfated, or become unstable and decompose when they undergo such a reaction.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1987 Feb
PMID:Species differences in the metabolism of N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine. 380 15

Numerous studies have indicated that two classes of cytosolic STs are involved in the bioactivation of procarcinogens and drugs to reactive electrophiles, especially in rodent tissues. These two classes of STs are the hydroxysteroid STs, which are involved in the conjugation of hydroxymethyl PAHs, and the phenol STs involved in the sulfation of alkenylbenzenes and N-hydroxyarylamines. Purification studies of rat liver STs have clearly indicated that specific isoforms of hydroxysteroid and phenol STs are capable of sulfating procarcinogens in vitro. Rat liver STa and BAST I are structurally similar hydroxysteroid STs, which have been shown to sulfate and bioactive HMBA. Molecular cloning studies of the rat hydroxysteroid STs indicate that these enzymes are probably part of a family of closely related genes. The single human hydroxysteroid ST that has been characterized is very similar to the rat enzymes, but its role in the bioactivation of hydroxymethyl PAHs has not been established. Phenol STs have been demonstrated to have an important role in the bioactivation of alkenylbenzenes and N-hydroxyarylamines. Purification of rat phenol STs has identified several different forms, but only some appear to be involved in bioactivation of procarcinogens. Four isoforms (HAST I and II, AST III and IV) are apparently responsible for the majority of N-hydroxyarylamine sulfation. The relationship between these enzymes has not been established but they may represent similar enzymes. Different isoforms of rat phenol ST are also involved in the bioactivation of procarcinogens and drugs. However, the role of these phenol STs, PST-1, Mx-ST, and paracetamol ST, in carcinogenesis requires further study. In human tissues, only two phenol STs, P-PST and M-PST, have been identified. The role of these enzymes or unidentified STs in the sulfation of N-hydroxyarylamine procarcinogens has not yet been established. Initial reports of the molecular cloning and expression of the rat and human phenol ST genes will provide a valuable mechanism for the characterization of roles of the individual enzymes in bioactivation.
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PMID:Biochemistry of cytosolic sulfotransferases involved in bioactivation. 806 57

Sulfation activity towards various heterocyclic and homocyclic aromatic hydroxamic acids and hydroxylamines was determined in adult human liver cytosol and with partially purified human liver sulfotransferases (STs). In adult human liver cytosols comparable ST activities towards N-hydroxy-2-acetyl-amino-5-phenylpyridine (N-OH-2AAPP), N-hydroxy-4-acetylaminobiphenyl (N-OH-4AABP) and N-hydroxy-4'fluoro-4-acetylaminobiphenyl (N-OH-4FAABP) were found, while the sulfation rates towards N-hydroxy-2-acetylaminofluorene (N-OH-2AAF), N-hydroxy-2-acetylaminonaphthalene (N-OH-2AAN), N-hydroxy-2-acetylaminophenanthrene (N-OH-2AAP) and N-hydroxy-4-acetylaminostilbene (N-OH-4AAS) were two- to five-fold lower. In adult liver cytosol ST activity was found towards all hydroxylamines tested. No significant differences were found for the various hydroxylamines. In general, the ST activities towards the various hydroxamic acids and hydroxylamines were comparable to phenol ST activity using adult liver cytosols. Partial purification of adult human liver STs was achieved by DEAE-Sepharose chromatography followed by anion exchange FPLC. Two separated protein peaks showing both N-OH-2AAPP and N-OH-2APP ST activities were observed and were designated human hydroxylamine/hydroxamic acid sulfotransferase (hHST) 1 and 2. Immunoblot analysis using an anti-rat estrogen ST antibody demonstrated cross reactivity with both hHSTs at a subunit mol. wt of 32 kDa corresponding to the phenol-sulfating form of phenol ST (P-PST). ST activity towards dopamine was low with both hHSTs, but hHST1 also contained significant capacity to sulfate dehydroepiandrosterone. The highest ST activity towards N-OH-2AAPP and N-OH-2APP was measured at pH 5.5 with both hHSTs. The Km values of the two hHSTs for sulfation of N-OH-2AAPP and N-OH-2APP were comparable, while the Vmax values for sulfation of N-OH-2APP were higher than for N-OH-2AAP with both hHSTs. FPLC anion exchange analysis of human platelet STs demonstrated that sulfation of N-OH-4ABP and N-OH-4AABP was associated with P-PST rather than M-PST (platelets do not possess any significant DHEA ST activity). Our results show that the various hydroxamic acids and hydroxylamines are converted by at least two hHSTs. The results presented here for the human liver hydroxamic acid and hydroxylamine ST activities are discussed in relation to those observed in the rat.
Carcinogenesis 1994 Jan
PMID:Sulfation of aromatic hydroxamic acids and hydroxylamines by multiple forms of human liver sulfotransferases. 829 46

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

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

The dose responses for several effects of low-level limited exposures to 2-acetylaminofluorene (AAF) in the livers of male Fischer 344 rats were measured and a subsequent phenobarbital tumor promotion regimen was used to manifest initiation of carcinogenesis. Three doses over a 10-fold range yielding cumulative total exposures of 0.126, 0.42, and 1.26 mmol AAF/kg body weight were achieved by daily intragastric instillation for up to 12 weeks with interim terminations. This was followed by 24 weeks administration of 500 ppm phenobarbital (PB) in the diet to promote liver tumor development. At 12 weeks at the end of AAF administration, all exposures produced adducts in liver DNA, measured by 32P postlabeling, and the level of adducts increased with exposure, except that the high exposure did not produce a dose proportional increase. Measurement of arylsulfotransferase activity, a key enzyme in the metabolic activation of AAF, revealed that in livers from the high exposure animals, the enzyme was inhibited. To assess for toxicity, the centrilobular zone of glutamine synthetase-positive hepatocytes was quantified immunohistochemically at 12 weeks. The area of the zone was reduced in the high exposure group and there was a trend to reduction in relationship to exposure. The two lower exposures to AAF produced no increase in cell proliferation, whereas the high exposure resulted in a marked increase, about 8-fold over controls. Initiation was assessed by induction of hepatocellular altered foci (HAF) that expressed the placental form of glutathione S-transferase. AAF induced HAF in the high exposure group, 9-fold at 8 weeks and 170-fold at 12 weeks compared to controls. In rats maintained on PB for 24 weeks after exposure, the multiplicity of HAF increased in controls and comparably in the low and mid exposure groups, but remained at the about the same high level in the high exposure group. The high exposure produced a substantial incidence of benign neoplasms by 12 weeks, and with promotion by 36 weeks, all rats developed hepatocellular neoplasia. In the mid exposure group, only one adenoma occurred at 36 weeks in 17 rats, while in the low exposure group, no liver tumor occurred in 23 rats. Thus, these findings document nonlinearities for some of the effects of AAF, with supralinear effects at the high exposure for cell proliferation and induction of HAF, and a no-observed-effect level for induction of promotable liver neoplasms at the lowest cumulative exposure of 0.126 mmol/kg, in spite of the formation of DNA adducts. We conclude that the effects of this DNA-reactive hepatocarcinogen leading to initiation exhibit nonlinearities and possible thresholds.
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PMID:Nonlinearities in 2-acetylaminofluorene exposure responses for genotoxic and epigenetic effects leading to initiation of carcinogenesis in rat liver. 984 22

Secreted and transmembrane proteins are critical to the cell-cell interactions governing normal development and carcinogenesis. To facilitate the identification of such molecules, we have developed a novel signal sequence trap that uses human placental alkaline phosphatase as a reporter. Libraries from mouse prostate and human prostatic carcinoma were constructed to test the PST (peptide signal trap) system, resulting in the identification of several secreted and transmembrane proteins.
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PMID:A new signal sequence trap using alkaline phosphatase as a reporter. 992 59

Carcinogen dose fractionation, diet and source of laboratory animal were examined as variables in the induction of colonic aberrant crypt foci (ACF) by the heterocyclic amine 2-amino-3-methylimidazo [4, 5-f]quinoline (IQ). In the first experiment, male F344 rats from the National Cancer Institute (NCI rats) were fed AIN-93G diet and, starting in the third week, IQ was given by gavage on alternating days, the total carcinogen dose of 105 mg being fractionated proportionally over 2, 4, 8 or 14 weeks. Only the high dose (2 week) treatment with IQ was effective for the induction of ACF at 16 weeks, producing on average 3.8 ACF/colon versus 0.5 ACF/colon in all other groups (P < 0.05). The 2 week IQ dosing protocol was used in a second experiment in which male F344 rats from Simonsen Laboratories (SN) or NCI were fed AIN-93G, AIN-76A or chow diet. On average, SN rats on chow diet had twice the number of aberrant crypts compared with NCI rats given the same diet and three to four times as many aberrant crypts as NCI rats fed AIN diets. Hepatic cytochrome P4501A1 (CYP1A1) levels were essentially unaffected by diet, but methoxyresorufin O-demethylase activities and CYP1A2 protein levels were increased 2- to 3-fold in animals fed chow versus AIN diets. During the 2 week period of carcinogen administration, IQ markedly induced CYP1A proteins and negated the differences among groups related to diet. No consistent diet-related changes were detected in the activities of aryl sulfotransferase or N-acetyltransferase, but UDP-glucuronosyltransferase activities were elevated 2- to 3-fold in rats given chow versus AIN diets. In summary, high dose treatment with IQ was required for the induction of ACF, rats on the chow diet had more aberrant crypts than those given AIN diets and male F344 rats purchased from different vendors and fed chow diet differed with respect to their sensitivity to induction of ACF.
Carcinogenesis 1999 Dec
PMID:Effect of carcinogen dose fractionation, diet and source of F344 rat on the induction of colonic aberrant crypts by 2-amino-3-methylimidazo[4,5-f]quinoline. 1059 Feb 22

The industrial solvent 2-nitropropane (2-NP) is a genotoxic hepatocarcinogen in rats. The genotoxicity of the compound in rats has been attributed to sulfotransferase-mediated formation of DNA-reactive nitrenium ions from the anionic form of 2-NP, propane 2-nitronate (P2N). Whether human sulfotransferases are capable of activating P2N is unknown. In the present study we have addressed this question by investigating the genotoxicity of P2N in various V79-derived cell lines engineered for expression of individual forms of human sulfotransferases, the phenol-sulfating and the monoamine-sulfating phenol sulfotransferases (hP-PST and hM-PST) and the human hydroxysteroid sulfotransferase (hHST). Genotoxicity was assessed by measuring the induction of DNA repair synthesis and by analyzing the formation of DNA modifications. P2N induced repair synthesis in V79-hP-PST and V79-hM-PST cells, whereas induction of repair synthesis in V79-hHST cells was negligible. P2N also resulted in the formation of 8-aminodeoxyguanosine and increased the level of 8-oxodeoxyguanosine in V79-hP-PST cells, but not in the parental V79-MZ cells, which do not show any sulfotransferase activity. Acetone oxime, the tautomeric form of the first reduction product of 2-NP, 2-nitrosopropane, was inactive in all cell lines. The results show that the human phenol sulfotransferases P-PST and M-PST are capable of metabolically activating P2N (P-PST >> M-PST) and that the underlying mechanism is apparently identical to that resulting in the activation of P2N in rat liver, where 2-NP causes carcinomas. These results support the notion that 2-NP should be regarded as a potential human carcinogen.
Carcinogenesis 2000 Feb
PMID:Human phenol sulfotransferases hP-PST and hM-PST activate propane 2-nitronate to a genotoxicant. 1065 71


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