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

The metabolic activation of the heterocyclic food carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) by two human cytochrome P450 monoxygenases (P4501A1 and P4501A2) and two human N-acetyltransferases (NAT1 and NAT2) was investigated. Various combinations of these enzymes were functionally expressed in COS-1 cells. DNA adducts resulting from the activation of IQ were assayed quantitatively by the 32P-postlabeling procedure. The highest adduct frequency was observed in cells expressing both CYP1A2 and NAT2. CYP1A2 in combination with NAT1 was 3-6 times less active. When expressed alone these enzymes gave rise to low adduct frequencies. Experiments with N-acetyl-IQ as substrate suggest that NAT1 and NAT2 in addition to their known role in N-acetylation display arylhydroxamic acid N, O-acetyltransferase (AHAT) activity. Quantitative differences in adduct formation between IQ and N-acetyl-IQ indicated that metabolic activation of these arylamines preferentially occurs by P4501A2-catalyzed N-hydroxylation followed by O-acetylation mediated through NAT1 and/or NAT2. These data, in combination with the known genetic polymorphism of NAT2, may explain the clinical observation that the acetylation polymorphism constitutes a risk factor in the carcinogenic activation of environmental mutagens.
Carcinogenesis 1992 Oct
PMID:The role of the human acetylation polymorphism in the metabolic activation of the food carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). 142 30

The possible roles of cytochrome P450 (P450) enzymes in the metabolic activation of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) by rat liver microsomes have been examined in a system containing the bacterial tester strain Salmonella typhimurium NM2009, a newly developed strain showing high O-acetyltransfer activities. The DNA-damaging activity could be determined by measuring expression of the umu gene in a plasmid containing the fused umuC-lacZ gene construct in the bacteria. The following lines of evidence support the view that both NDMA and NDEA are principally oxidized to reactive products by P450 2E1 in rat liver microsomes. First, NDMA and NDEA were activated by rat liver microsomes in a protein- and substrate-dependent manner and the former chemical was more active than the latter; both activities were induced in rats treated with P450 2E1 inducers such as ethanol, acetone and isoniazid and by starvation. Second, activation of NDMA and NDEA were both inhibited significantly by antibodies raised against rat P450 2E1 and by P450 2E1 inhibitors such as diethyldithiocarbamate and 4-methylpyrazole in rat liver microsomes. Finally, in reconstituted monooxygenase systems containing purified rat P450 enzymes, P450 2E1 gave the highest rates of the activation of both NDMA and NDEA; the addition of rabbit cytochrome b5 to the system caused about a 1.5-fold increase in both reactions. In separate experiments we also found that N-nitrosomethylacethoxymethylamine, a compound that reacts with DNA after ester cleavage, is more genotoxic in S.typhimurium NM2009 than in S.typhimurium NM2000, a strain that is defective in O-acetyltransferase activity. Part of the pathway involved in the activation of nitrosamines is suggested to be acetylation of alkyldiazohydroxides formed by P450 or acetylesterase, because the genotoxic activity of N-nitrosomethylacethoxymethylamine in S.typhimurium NM2009 could be inhibited by the O-acetyltransferase inhibitor pentachlorophenol. These results indicate that NDMA and NDEA are oxidized to gentoxoic products by rat liver microsomes and that a P450 2E1 enzyme plays a major role in the activation of these two potent carcinogens. The activation pathway of N-nitrosodialkylamines through acetylation by O-acetyltransferase has been proposed. This simple bacterial system for measuring genotoxicity should facilitate studies on the activation of N-nitroso alkylamines.
Carcinogenesis 1992 Jun
PMID:Participation of rat liver cytochrome P450 2E1 in the activation of N-nitrosodimethylamine and N-nitrosodiethylamine to products genotoxic in an acetyltransferase-overexpressing Salmonella typhimurium strain (NM2009). 160 Jun 20

Epidemiological studies have shown that there is a significantly greater proportion of the rapid acetylator phenotype in patients with colorectal tumors than in controls; phenotype-related differences in bioactivation of dietary or environmental amines in the intestinal epithelium have been suggested as a mechanism for this effect. In the present study, we have used hepatic and intestinal cytosols to compare N-acetyltransferase (NAT1 and NAT2), O-acetyltransferase (OAT) and arylhydroxamic acid N,O-acyltransferase (AHAT) distribution in rapid and slow acetylator rabbits. The ratio (rapid/slow) for p-aminobenzoic acid acetylation (a selective substrate for NAT1) was 6 in liver, 1.7-2 in small intestine and 1.3-1.5 in large intestine while the ratio of sulfamethazine acetylation (a selective substrate for NAT2) was 150 in liver, 16-22 in small intestine and 1.8-2.5 in large intestine. The ratios (rapid/slow) for DNA binding of N-hydroxy-3,2'-dimethyl-4-aminobiphenyl and N-hydroxy-4-aminobiphenyl (primarily substrates for OAT) were 82-84 in liver, 13-20 in small intestine and 3.8-5.3 in large intestine and for DNA binding of N-hydroxy-2-acetylamidofluorene (a substrate for AHAT), the ratio was 432 in liver, 32-161 in small intestine and 8.8-13.5 in large intestine. The data show also that NAT1 activity is uniformly distributed along the intestinal tract whereas NAT2 activity is highest in the small intestine. In addition, hepatic and intestinal OAT and AHAT but not NAT1 activities in the rabbit intestine are similarly distributed to activities for NAT2, suggesting that NAT2, OAT and AHAT activities are properties of a single protein in the rapid acetylator phenotype. Moreover, OAT and AHAT activities were much higher in tissues from the rapid than the slow phenotype. The data support the hypothesis that phenotype-dependent metabolic activation of N-OH heterocyclic or aromatic amines to reactive acetoxy metabolites may be involved in the etiology of colorectal cancer.
Carcinogenesis 1991 Aug
PMID:Distribution of acetyltransferase activities in the intestines of rapid and slow acetylator rabbits. 186 Jan 67

The metabolic activation of the food-borne rodent carcinogens 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1) was compared with that of the known human carcinogen 4-aminobiphenyl (ABP), using human liver microsomes, human and rat liver cytosols, and human colon cytosol. All of these aromatic amines were readily activated by N-hydroxylation with human liver microsomes (2.3-5.3 nmol/min/mg protein), with PhIP and ABP exhibiting the highest rates of cytochrome P450IA2-dependent N-oxidation, followed by MeIQx, IQ and Glu-P-1. In contrast, while ABP and 2-aminofluorene were readily N-acetylated (1.7-2.3 nmol/min/mg protein) by the polymorphic human liver cytosolic N-acetyltransferase, none of the heterocyclic amines were detectable as substrates (less than 0.05 nmol/min/mg protein). Likewise, only low activity was observed (0.11 nmol/min/mg protein) for the N-acetylation of p-aminobenzoic acid, a selective substrate for the human monomorphic liver N-acetyltransferase. The radiolabeled N-hydroxy (N-OH) arylamine metabolites were synthesized and their reactivity with DNA was examined. Each derivative bound covalently with DNA at neutral pH (7.0), with highest levels of binding observed for N-OH-IQ and N-OH-PhIP. Incubation at acidic pH (5.0) resulted in increased levels of DNA binding, suggesting formation of reactive arylnitrenium ion intermediates. These N-OH arylamines were further activated to DNA-bound products by human hepatic O-acetyltransferase. Acetyl coenzyme A (AcCoA)-dependent, cytosol-catalyzed DNA binding was greatest for N-OH-ABP and N-OH-Glu-P-1, followed by N-OH-PhIP, N-OH-MeIQx and N-OH-IQ; and both rapid and slow acetylator phenotypes were apparent. Rat liver cytosol also catalyzed AcCoA-dependent DNA binding of the N-OH arylamines; and substrate specificities were comparable to human liver, except that N-OH-MeIQx and N-OH-PhIP gave relatively higher and lower activities respectively. Human colon cytosols likewise displayed AcCoA-dependent DNA binding activity for the N-OH substrates. Metabolic activity was generally lower than that found with the rapid acetylator liver cytosols; however, substrate specificity was variable and phenotypic differences in colon O-acetyltransferase activity could not be readily discerned. This may be due, at least in part, to the varied contribution of the monomorphic acetyltransferase, which would be expected to participate in the enzymatic acetylation of some of these N-OH arylamines.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1991 Oct
PMID:Metabolic activation of carcinogenic heterocyclic aromatic amines by human liver and colon. 193 65

1-Amino-8-nitropyrene (1,8-ANP), a product of 1,8-dinitropyrene metabolism by either bacterial or mammalian enzymes, is weakly mutagenic to the 'classical nitroreductase'-deficient Salmonella tester strain TA98NR. The addition to the test system of rat liver cytosol without cofactors did not produce any effect on the 1,8-ANP mutagenic response toward TA98NR strain. Conversely, when both rat hepatic cytosol and NADPH (1 mM) were added to the mutagenicity assay, a 10-fold increase in 1,8-ANP mutagenic activity was observed. This suggests the involvement of rat hepatic cytosolic NADPH-dependent nitroreductase(s) in 1,8-ANP mutagenic activation. The addition to the mutagenesis assay of pentachlorophenol, an inhibitor of O-acetyltransferase and sulfotransferase, produced a dose-dependent decrease of 1,8-ANP mutagenic activation, whereas 2,6-dichloro-4-nitrophenol, a more specific inhibitor of sulfotransferase than O-acetyltransferase, did not affect the activation of 1,8-ANP to a mutagen at concentrations that selectively inhibit only bacterial sulfotransferase. This indicates that bacterial O-acetyltransferase but not sulfotransferase plays a role in the mutagenic activation of 1,8-ANP. Addition of acetyl co-enzyme A (AcCoA) and adenosine 3'-phosphate 5'-phosphosulfate (PAPS), cofactors for O-acetyl-transferase and sulfotransferase respectively, to the test system caused a dose-dependent inhibition of 1,8-ANP mutagenic activation by rat liver cytosol and NADPH, probably due to the formation of highly reactive O-acetoxy and N-sulfate ester derivatives of 1,8-ANP, which react with nucleophilic sites before reaching bacterial DNA. This hypothesis was confirmed by DNA covalent binding in in vitro experiments showing that both the cofactors AcCoA and PAPS enhanced the NADPH/rat liver cytosol-mediated covalent binding of 1,8-ANP to DNA from calf thymus 10- and 3-fold respectively. It seems likely that rat hepatic cytosolic nitroreductases activate 1,8-ANP to an N-hydroxyarylamine derivative which can be further metabolized to mutagenic species by either bacterial or mammalian O-acetyltransferase.
Carcinogenesis 1991 Feb
PMID:Effect of rat liver cytosolic enzymes and cofactors on mutagenicity of 1-amino-8-nitropyrene. 199 97

Solutions of several promutagens or of non-genotoxic carcinogens were exposed to sunlight or to artificial sources of UV or fluorescent light, under various experimental conditions. Irradiation resulted in the oxygen-mediated formation of direct-acting mutagenic and DNA-damaging photoproducts in bacteria, with evident structure-activity relationship. Of the aromatic amines tested, 2-aminofluorene and, with lower efficiency, 2-acetylaminofluorene were photoactivated, whereas irradiation of 4-acetylaminofluorene and of the 1- and 2-amino substitutes of anthracene and naphthalene did not produce mutagenic derivatives in Salmonella typhimurium. Of the heterocyclic amines, 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-3,4-dimethylimidazo[4,5-f]quinoline were extraordinarily sensitive to activation by sunlight and fluorescent light, which contrasted with the insensitivity of the tryptophan pyrolysis products. Use of optical and interference filters showed that near-UV light is the main component of solar radiation responsible for the formation of highly stable mutagenic derivatives. The mutagenicity of 2-aminofluorene and of the aminoimidazoquinoline compounds, following both metabolic and light activation, was lost in nitroreductase- and O-acetyltransferase-dificient bacteria. Benzo[alpha]pyrene was better activated by 254- than by 365-nm UV light. Sunlight did not affect the lack of mutagenicity of carcinogenic organochlorine pesticides, but exposure to 254-nm UV light selectively resulted in the formation of weak mutagens from dieldrin and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene, but not from 4,4'-dichlorodiphenyltrichloroethane, lacking carbon-carbon double bonds.
Carcinogenesis 1989 Jun
PMID:Photoactivation of mutagens. 265 63

Microsomes from ram seminal vesicles known as a rich source of prostaglandin H synthase (PHS) activate the food mutagen IQ (2-amino-3-methylimidazo[4,5-f]quinoline) to (a) product(s) mutagenic in Salmonella typhimurium TA98. The activation is dependent on the PHS cofactor arachidonic acid and is strongly inhibited by the PHS inhibitor indomethacin. In this system, the mutagenic potency of IQ is 22 and 110 times higher than that of 2-aminofluorene and benzidine, respectively. The high mutagenic potency of IQ observed previously with mono-oxygenase activation is thus extended to the PHS system. The mutagenic activity produced by PHS increases for 4 h; this contrasts with the relatively short lifetime of the activity produced by mono-oxygenase and suggests that different agents are involved in the two processes. The PHS-mediated mutagenic activity of IQ is strongly dependent on the bacterial O-acetyltransferase which is defective in strain TA98/1,8-DNP6. Further, the responses of the strains TA1978 and TA1538 indicate that the mutagenic activity is dependent on lack of the bacterial DNA excision repair and independent of the plasmid pkM101 coded error-prone DNA repair system. Structural analogs of IQ without a methyl group on the imidazole ring and with a naphthalene instead of the quinoline ring show greatly diminished PHS-mediated mutagenic activity. The strain response pattern and structure-activity relationships are similar to those found with mono-oxygenase activation of IQ and thus indicate a basic similarity of the IQ activation via PHS with that via mono-oxygenase. It is hypothesized that PHS may activate carcinogenic heterocyclic aromatic amines in vivo.
Carcinogenesis 1987 Apr
PMID:Prostaglandin H synthase-dependent mutagenic activation of heterocyclic aromatic amines of the IQ-type. 310 46

The 2-hydroxyamino-3-methylimidazolo[4,5-f]quinoline (N-hydroxy-IQ), a metabolite of the food mutagen--carcinogen IQ, was mutagenic to Salmonella TA98 (nitroreductase deficient). When either rat hepatic cytosol, NADPH (1 mM) or ascorbate (0.5 mM) was added to the mutagenicity assay, mutagenicity increased up to 15-, 10- and 50-fold respectively. In light of the effects of ascorbate and NADPH, it appears likely that hepatic cytosol may contain factors that protect N-hydroxy-IQ from oxidative decomposition. In contrast, hepatic monooxygenase metabolism of N-hydroxy-IQ decreased mutagenicity. When pentachlorophenol, an inhibitor of O-acetyltransferase and sulfotransferase, was added to the mutagenicity assay, a dose-dependent inhibition of N-hydroxy-IQ mutagenicity was observed. 2,6-Dichloro-4-nitrophenol, a more specific inhibitor of sulfotransferase than O- acetyltransferase, did not inhibit the mutagenicity of N-hydroxy-IQ at concentrations which appear to selectively inhibit only bacterial sulfotransferase. The data suggest that bacterial O-acetyltransferase rather than sulfotransferase mutagenically activates N-hydroxy-IQ. N-hydroxy-IQ covalently bound to calf thymus DNA in vitro under non-enzymatic conditions at pH 7.4. Rat hepatic cytosolic O-acetyltransferase and sulfotransferase enhanced the covalent binding of N-hydroxy-IQ to DNA 30- and 5-fold respectively. The data suggest that the mutagenicity of N-hydroxy-IQ is due to the reactivity of N-hydroxy-IQ with DNA and the ability of N-hydroxy-IQ to be further activated by bacterial O-acetyltransferase.
Carcinogenesis 1988 Mar
PMID:Mutagenicity and in vitro covalent DNA binding of 2-hydroxyamino-3-methylimidazolo[4,5-f]quinoline. 316 8

A genetic polymorphism in S-acetyl coenzyme A (AcCoA)-dependent N-acetyltransferase has been associated with a differential risk for certain cancers in humans. In this study, several tissues from the inbred Syrian hamster with a genetically defined AcCoA-dependent N-acetyltransferase polymorphism (homozygous rapid acetylator, Bio. 87.20; homozygous slow acetylator, Bio. 82.73/H; and heterozygous acetylator, Bio. 87.20 X Bio. 82.73/H F1), were investigated for the relationship of arylamine N-acetyltransferase to the AcCoA-dependent metabolic activation of carcinogenic N-hydroxy (N-OH)-arylamines to bind to DNA (O-acetyltransferase). The levels of both 2-aminofluorene (AF) N-acetyltransferase and N-OH-AF O-acetyltransferase activity reflected the N-acetylator genotype in liver, intestine, kidney and lung cytosols. A significant acetylator gene--dose response for AF N-acetyltransferase and N-OH-AF O-acetyltransferase activities was observed in liver and lung cytosols. In contrast, acetylator genotype was not consistently expressed for the AcCoA-dependent N-acetylation of 4-aminobiphenyl (ABP), nor for the AcCoA-dependent metabolic activation of N-OH-ABP and N-OH-3,2'-dimethyl-4-aminobiphenyl in these same tissue cytosols. Two peaks of acetyltransferase activity were partially purified by ion exchange FPLC chromatography from the hepatic cytosol of both the homozygous rapid and homozygous slow acetylator hamster. In contrast to unfractionated cytosol, the isozyme(s) eluting first clearly demonstrated levels of AcCoA-dependent arylamine N-acetyltransferase and N-OH-arylamine O-acetyltransferase activities that were consistent with N-acetylator genotype (polymorphic) for all substrates tested. In contrast, the slower eluting isozyme(s) in each acetylator cytosol showed levels of AcCoA-dependent N- and O-acetyltransferase activities that did not vary with N-acetylator genotype (monomorphic). The AcCoA-dependent O-acetyltransferase activity of both the monomorphic and polymorphic peaks was paraoxon resistant. These studies demonstrate acetylator genotype-dependent control of AcCoA-dependent metabolic activation of N-OH-arylamines(O-acetylation) by polymorphic isozyme(s) similar to that for AcCoA-dependent N-acetylation of arylamines in the hamster. The polymorphic genetic control of N-OH-arylamine O-acetyltransferase may be an important risk factor for arylamine-induced cancer, in those species and tissues expressing appreciable levels of O-acetyltransferase activity.
Carcinogenesis 1987 Dec
PMID:Acetylator genotype-dependent metabolic activation of carcinogenic N-hydroxyarylamines by S-acetyl coenzyme A-dependent enzymes of inbred hamster tissue cytosols: relationship to arylamine N-acetyltransferase. 367 3

A genetic polymorphism in the enzymatic N-acetylation of sulfamethazine and other drugs in humans is well known and has been related to differential susceptibility to drug toxicities. Carcinogenic aromatic amines such as 2-aminofluorene also undergo N-acetylation, and phenotypic slow acetylator individuals have been suggested to be at increased risk to arylamine-induced urinary bladder cancer. However, acetyltransferases have also been shown to catalyze a final metabolic activation step in the conversion of both hydroxamic acid (e.g. N-hydroxy-N-acetyl-2-aminofluorene N,O-acyltransferase) and N-hydroxy-arylamine (e.g. N-hydroxy-2-aminofluorene O-acetyltransferase) metabolites to DNA-bound adducts. In this regard, rapid acetylators have recently been reported to be at higher risk for colorectal cancer. In this study, we examined the enzymatic activity of 35 human liver cytosol samples (obtained surgically from organ donors) for sulfamethazine and 2-aminofluorene N-acetyltransferase activities, N-hydroxy-N-acetyl-2-aminofluorene N,O-acyltransferase activity, and the acetyl coenzyme A (CoA)-dependent O-acetylation of N-hydroxy-2-aminofluorene to form DNA-bound products. The results with sulfamethazine indicated that about two-thirds of the human liver samples were of the slow acetylator phenotype; the same individuals also exhibited levels of 2-aminofluorene N-acetylation that were consistent with their respective sulfamethazine-N-acetylation activity. N-Hydroxy-N-acetyl-2-aminofluorene N,O-acyltransferase activity was not detected. However, the acetyl CoA-dependent activation of N-hydroxy-2-aminofluorene was observed for nearly all of the samples and was consistently higher in the fast acetylator group. These data support the hypothesis that phenotypic rapid acetylator individuals are likely to be at higher risk to aromatic amine-induced cancers in those tissues containing appreciable levels of N-hydroxy arylamine O-acetyltransferase.
Carcinogenesis 1987 Dec
PMID:The S-acetyl coenzyme A-dependent metabolic activation of the carcinogen N-hydroxy-2-aminofluorene by human liver cytosol and its relationship to the aromatic amine N-acetyltransferase phenotype. 367 22


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