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)

The experiments reported here were undertaken to ascertain whether the principle of the selection and rapid emergence of carcinogen-initiated cells based on their resistance to cytotoxicity demonstrated in rat liver is applicable to hamster pancreas. Hamsters injected with a single dose of 70 mg/kg body weight of the pancreatic carcinogen, N-nitrosobis(2-oxopropyl)amine, were subjected to pancreatic injury and regeneration induced by DL ethionine followed by methionine rescue while on a continuous daily regimen of 10 mg/kg body weight of N-nitroso-2,6-dimethylmorpholine by gavage. Randomly selected animals were killed weekly from the 4th week following the induction of regeneration through the 10th week. This carcinogenic schedule significantly decreased the time of emergence of cell injury, cell death, and proliferative, preneoplastic, and neoplastic lesions of the exocrine pancreas. Carcinoma in situ and invasive adenocarcinoma of pancreatic ducts appeared during the 7th and 8th week after induction of pancreatic regeneration, earlier than results obtained with multiple dose carcinogenesis experiments.
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PMID:Pancreatic lesions induced by a single dose of N-nitrosobis(2-oxopropyl)amine and selection by resistance to cytotoxicity. 378 14

When male Fischer rats were fed Purina chow supplemented with 2% D,L-methionine and 1% choline chloride, the rapid increase in N2-guanine tRNA methyltransferase II (NMG2) activity otherwise seen in response to cancer-promoting doses (0.02% in the diet) of 2-acetylaminofluorene (AAF) was prevented, and the increase in NMG2 activity otherwise caused by carcinogenic doses of AAF (0.06% in the diet) was decreased by 50%. In addition, the return of NMG2 activity to a normal level after completion of a 3-week regimen of 0.06% AAF was accelerated in animals fed the methionine plus choline supplemented diet. As shown earlier in this laboratory, liver tRNA methylating enzyme activities are shifted rapidly to an onco-fetal pattern in rats receiving methyl-deficient diets. This pattern is characterized by selectively elevated NMG2 activity while the activities of other base-specific tRNA methylating enzymes are relatively unchanged. Our combined results indicate that the exogenous supply of methyl groups is a factor in regulating NMG2 activity and can modulate at least one response of animals to carcinogens.
Carcinogenesis 1987 Apr
PMID:Suppression by methionine and choline of onco-fetal patterns of liver tRNA methyltransferase activities in carcinogen-treated rats. 382 24

Administration of the hepatotoxin and carcinogen, inorganic hydrazine, to rodents results in the formation of 7-methylguanine and O6-methylguanine in liver DNA; co-administration of [methyl-14C]methionine or [14C]formate with the hydrazine labels the methylguanines, suggesting involvement of the 1-carbon pool in the methylation process. The present study investigates the proposal that the methylation mechanism involves reaction of hydrazine with endogenous formaldehyde to yield formaldehyde hydrazone, which could be metabolized to the potent methylating agent diazomethane. Hamsters were pretreated with methanol, ethanol or cyanamide to alter the endogenous hepatic aldehyde levels prior to administration of hydrazine. Formaldehyde levels were refractory to the pretreatments; hepatic acetaldehyde levels were increased, but hydrazine administration under such conditions did not result in the formation of ethylated guanines in DNA. Methanol and ethanol inhibited hydrazine-induced methylation of DNA. Hydrazine incubated with liver S9 fraction and calf thymus DNA induced the formation of 7-methylguanine and O6-methylguanine when formaldehyde was present in the incubation system; substitution of formaldehyde with acetaldehyde in the incubation medium did not result in any detectable alkylation of DNA. Both liver microsomal and cytosolic fractions demonstrated heat-labile activity in supporting the hydrazine-induced methylation process. Tetraformyltrisazine, or a similar reaction product of hydrazine and formaldehyde, may be a more important intermediate than formaldehyde hydrazone in the hydrazine-induced methylation of DNA.
Carcinogenesis 1986 Mar
PMID:The role of formaldehyde in hydrazine-induced methylation of liver DNA guanine. 394 26

A diet that is deficient in methionine, choline, folic acid and vitamin B12 has been found to induce alterations rapidly in liver tRNA methylation in male Fischer rats. In vitro assays indicated that activity of N2-guanine tRNA methyltransferase II (NMG2) was increased to 150% of controls levels in 1 week and 300% of control levels after 2 weeks or longer on this diet. Incompletely methylated tRNA was isolated from livers of these same animals, indicating that there was impairment of methylation in vivo. The effects on liver tRNA methylation of this methyl-deficient diet were thus seen to mimic those of the liver carcinogen, ethionine, which also causes production of hypomethylated tRNA and increased activity of NMG2. The effect of the same diet on liver tRNA methyltransferase activity of C57BL/6J and C3H/HeJ inbred mice were also studied. Intake of the lipotrope-deficient diet induced elevation in activity of liver N2-guanine tRNA methyltransferase II activity in C57BL/6J mice, similar to that seen in rats. In contrast, the methyl-deficient diet had very little effect on the same enzyme activity in C3H/HeJ animals.
Carcinogenesis 1986 Mar
PMID:Altered tRNA methylation in rats and mice fed lipotrope-deficient diets. 394 30

A new method was devised to study adduct formation of N-acetyl-L-methionine (N-Ac-met) with activated species of the carcinogen N-hydroxy-2-acetylaminofluorene (N-OH-2-AAF). Following degradation of the adducts, the isomeric methylthio derivatives of 2-acetylaminofluorene (2-AAF) and 2-aminofluorene (2-AF) were separated and quantified by h.p.l.c. With the use of this method the nucleophilicity of N-Ac-met toward enzymatically produced N-acetoxy and N-sulfonoxy derivatives of 2-AF and 2-AAF, respectively, and toward the synthetic model ester, N-acetoxy-2-acetylaminofluorene (N-OAc-2-AAF), was determined. For comparison, the interaction of tRNA and polyguanylic acid (poly G) with the above compounds was measured by standard procedures. tRNA was an efficient acceptor of enzymatically formed N-acetoxy and N-sulfonoxy derivatives as well as of N-OAc-2-AAF. The nucleophilicity of N-Ac-met toward enzymatically formed N-sulfonoxy-2-AAF was comparable with that of tRNA. However, its reactivity with N-OAc-2-AAF and enzymatically generated N-acetoxy-2-aminofluorene (N-OAc-2-AF) was only 20% of that of tRNA. Poly G was as reactive as tRNA toward synthetic N-OAc-2-AAF and enzymatically generated N-OAc-2-AF but was only 25% as efficient as tRNA or N-Ac-met in accepting enzymatically formed N-sulfonoxy-2-AAF. The difference in the interaction of the three nucleophiles with N-OAc-2-AAF and N-OAc-2-AF compared with N-sulfonoxy-2-AAF indicate that N-OAc-2-AAF is not a general model of the ultimate electrophilic metabolites of 2-AAF. Studies of the kinetics of the interaction of N-OAc-2-AAF with N-Ac-met, tRNA and poly G demonstrated dependence of adduct formation on nucleophile concentration, indicative of a bimolecular mechanism. Arylamidonium or nitrenium ions are therefore not necessarily the ultimate electrophilic metabolites of 2-AAF obligatory for interaction with cellular nucleophiles. There was no evidence that nitrenium ions are intermediates in the cytosolic reduction of N-OH-2-AAF to 2-AAF.
Carcinogenesis 1985 Feb
PMID:Interaction of nucleophiles with the enzymatically-activated carcinogen, N-hydroxy-2-acetylaminofluorene, and with the model ester, N-acetoxy-2-acetylaminofluorene. 397 91

3,3-[3H]Dimethyl-1-phenyltriazene, 1-(4-chlorophenyl)-3,3-[3H]dimethyltriazene and 3,3-[3H]dimethyl-1-(2,4,6-trichlorophenyl)-triazene methylate initiator tRNA in vitro only after pre-incubation with microsomal enzymes and NADPH. The finding confirms that procarcinogenic dialkyl aryltriazenes must be enzymatically converted into reactive metabolites, presumably into the corresponding monoalkyltriazenes, which ultimately react with tRNA. The methylation at 37 degrees C requires 40-60 min and individual triazenes showed differential alkylating capacity if tRNA was the limiting factor. Enzymatic hydrolysis of the modified initiator tRNA, followed by separation of nucleosides on Sephadex G10 or Dowex 50 columns, revealed that 7-methylguanosine was the principal labelled product. The methylated tRNA showed a significantly increased acceptance for L-methionine. It appears that methylation of initiator tRNA at N7 of guanine affected the conformation of initiator tRNA and rendered the nucleic acid more accessible for cognate aminoacyl-tRNA synthetase.
Carcinogenesis 1985 Jul
PMID:Microsome-mediated alkylation of rat liver initiator tRNA by 3,3-dimethyl-1-phenyltriazene and its ring-chlorinated derivatives. 401 80

1. The incorporation of methyl groups into histones from dimethylnitrosamine and from methionine was studied by injection of the labelled compounds, isolation of rat liver and kidney histones, and analysis of hydrolysates by column chromatography. 2. Labelled methionine gave rise to labelled in-N-methyl-lysine, di-in-N-methyl-lysine and an amino acid presumed to be omega-N-methyl-arginine. 3. Administration of labelled dimethylnitrosamine gave rise to labelled S-methylcysteine, 1-methylhistidine, 3-methylhistidine and in-N-methyl-lysine derived from the alkylating metabolite of dimethylnitrosamine. In addition, labelled formaldehyde released by metabolism of dimethylnitrosamine leads to the formation of labelled S-adenosylmethionine, and hence to labelling of in-N-methyl-lysine, di-in-N-methyl-lysine and omega-N-methylarginine by enzymic methylation. 4. The formation of in-N-methyl-lysine by alkylation of liver histones was confirmed by using doubly labelled dimethylnitrosamine to discriminate between direct chemical alkylation and enzymic methylation via S-adenosylmethionine. These experiments also suggested the possibility that methionine residues in the histones were alkylated to give methylmethionine sulphonium residues. 5. The extent of alkylation of liver histones was maximal at about 5h after dosing and declined between 5 and 24h. The methylated amino acids resulting from direct chemical alkylation were preferentially lost: this is ascribed to necrosis of the more highly alkylated cells. 6. Liver histones were about four times as alkylated as kidney histones; the extent of alkylation of liver histones was similar to that of liver total nuclear proteins. 7. Methyl methanesulphonate (120mg/kg) alkylated liver histones to a greater extent than did dimethylnitrosamine. Diethylnitrosamine also alkylated liver histones. 8. The results are discussed with regard to the possible effects of alkylation on histone function, and the possible role of histone alkylation in carcinogenesis by the three compounds.
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PMID:Methylation of nuclear proteins by dimethylnitrosamine and by methionine in the rat in vivo. 513 29

Feeding a choline deficient methionine low (CLD) diet for two weeks can substitute for partial hepatectomy in the genesis with benzo[a]pyrene (B[a]P) or 1,2-dimethylhydrazine (1,2-DMH) of resistant hepatocytes that can be selected with dietary 2-acetylaminofluorene plus partial hepatectomy. With single doses of B[a]P or 1,2-DMH during the feeding of the CLD diet for 3 weeks, the number of foci of hepatocytes positive for gamma-glutamyl transferase is approximately the same as with the same dose of each carcinogen given after partial hepatectomy. DL-ethionine was now found to be positive when given as a single dose to animals on the CLD diet. Feeding ethionine for 6 or 12 weeks in a similar choline lipotrope deficient diet also induced a significant increase in foci of enzyme altered hepatocytes. The results indicate that dietary imbalance can have an important influence on initiation of chemical carcinogenesis.
Carcinogenesis 1983
PMID:The induction of resistant hepatocytes during initiation of liver carcinogenesis with chemicals in rats fed a choline deficient methionine low diet. 630 37

The ability of methyl-deficient, amino acid-defined diets to produce liver tumors was studied in rats treated both with and without initiating doses of diethylnitrosamine (DENA). Male, weanling F344 rats were fed a complete, amino acid-defined diet for one week. They were then injected once i.p. with one of 3 doses of DENA (20, 70 or 200 mg/kg body weight) and fed the complete diet for an additional week. Thirty animals from each dose group were then maintained for 76 weeks on the complete diet (Diet 1) or one of 4 methyl-deficient diets: Diet 2, devoid of methionine and choline; Diet 3, devoid of methionine only; Diet 4, devoid of choline only and Diet 5, devoid of methionine, choline, folic acid and vitamin B12. In Diets 2, 3 and 5 methionine was replaced by equimolar amounts of its metabolic precursor DL-homocystine. Control rats were injected i.p. with the saline vehicle and maintained for the 76-week period on Diets 1 and 2. Forty percent of the rats fed Diet 2, but receiving no DENA, developed hepatocellular carcinomas or cholangiomas. A 90-100% incidence of hepatocellular carcinomas was seen in all groups initiated with DENA and fed Diet 2. No malignant liver tumors developed in Diet 1 rats that had received 0 or 20 mg/kg DENA; however, hepatocellular carcinomas were noted in one-half of such animals receiving the 70 and 200 mg/kg doses. Liver metastases grew in the lungs of 60% of the tumor-bearing rats fed Diet 2; none were seen in the Diet 1-fed rats. The singly deficient Diets 3 and 4 enhanced liver tumor formation to DENA-initiated rats to a significantly lesser extent than did Diet 2. All DENA-initiated rats fed the severely deficient Diet 5, died within 23 experimental weeks with livers containing hepatocytes of atypical appearance and, particularly at the 2 higher dosages, a cirrhotic pseudonodular architecture. No hepatocellular carcinomas or cholangiomas were observed in Diet 5-fed rats. None of the diets tested appeared to enhance tumor formation in extrahepatic tissues. In fact, significant decreases were noted in the formation of spontaneous testicular interstitial cell tumors in Diet 2-fed rats and of pancreatic acinar tumors in rats fed Diets 2 and 3. Diet 2, devoid of both methionine and choline, also induced metaplasia of pancreatic acinar cells to hepatocyte-like cells and was associated with moderate to severe hyperplasia of the transitional epithelium lining the renal pelvis.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1983 Dec
PMID:Hepatocarcinogenesis in rats fed methyl-deficient, amino acid-defined diets. 631 18

Earlier studies from this laboratory of the metabolism of 7,12-dimethylbenz[a]anthracene (DMBA) and of benzo[a]pyrene as well as studies of mutagenic and carcinogenic activity of some of the metabolic products led to the concept that a necessary first step in carcinogenesis by most alkyl substituted polycyclic hydrocarbons is biotransformation to a meso-anthracenic hydroxyalkyl metabolite, whereas most hydrocarbons lacking alkyl substituents undergo a bio-alkylation substitution reaction in the mesoanthracenic position(s) or L-region as a necessary first step in carcinogenesis. According to this unified hypothesis, all strong polycyclic hydrocarbon carcinogens must either, themselves, bear a meso-anthracenic alkyl substituent or else undergo a bio-alkylation substitution reaction in vitro and in vivo. Here we report that the weak carcinogen benz[a]anthracene undergoes meso-anthracenic methylation by S-adenosyl-L-methionine (SAM), in the presence of a rat liver cytosol preparation, in vitro, to form DMBA and presumably the moderately active carcinogens 7-methylbenz[a]anthracene and 12-methylbenz[a]anthracene. These compounds are substrates for further L-region methylation to form the strong carcinogen, DMBA.
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PMID:Biosynthesis of the potent carcinogen 7,12-dimethylbenz[a]anthracene. 643 68


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