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)

N.m.r. spectroscopy demonstrates that N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) exists as a mixture of four isomers, A, B, C and D, the equilibrium ratios of which are 57:8:16:19, respectively, at 25 degrees C. Two of these isomers, A and B, are rotomers of the open chain conformer, while the other two, C and D, are rotomers of the ring tautomer of HPOP and are derived from A and B, respectively, via an intramolecular cyclization reaction. A syn orientation of the nitroso and carbonyl groups favors an open chain configuration (isomer A), while an anti orientation favors cyclization of the molecule (isomer D). Two forms of HPOP (I and II) which are mixtures of isomers A and C, and D and B, respectively were separated chromatographically. These two forms interconvert to each other. The first rate order constants for the interconversion reactions were determined to be 4.7 X 10(-3) and 12.8 X 10(-3)/min, respectively. During these reactions isomers A and D interconvert via the intermediate formation of isomer C. This suggests that rotomerization of C and D is thermodynamically more favorable than rotomerization of their open-chain tautomers A and B, and suggests an intramolecular interaction between the carbonyl and nitroso groups. Isomers A and D are formed during the metabolism of N-nitrosobis(2-oxopropyl)amine (BOP) and cis N-nitroso-2,6-dimethylmorpholine (NNDM), respectively, by hamster liver microsomes and NADH or NADPH. The stereo-specificity of reduction of BOP and the hydroxylation of cis NNDM results in the formation of two slowly interconvertible isomers of HPOP. This, in combination with a possible different metabolic fate of the cyclic and open tautomers of this compound, may have a significant impact on the mechanism of activation of pancreatropic nitrosamines which share HPOP as a common metabolite.
Carcinogenesis 1987 Jan
PMID:Structural relationships of pancreatic nitrosamine carcinogens. 380 97

We have studied the irreversible binding of [14C]estradiol to hamster liver and kidney microsomes of castrated hamsters. The binding of estradiol metabolites to kidney microsomes was approximately 25 times lower than seen for liver microsomes, and was not affected by increases in protein or substrate concentration. Our results indicate that this irreversible binding, covalent in nature, is dependent on the metabolism of estrogens to catechols since the absence of NADPH markedly reduces this binding. The irreversible binding was inhibited nearly 70% by addition of catechol-O-methyl transferase (COMT) and S-adenosylmethionine (SAM). Ascorbic acid also inhibited the binding to 85% in a dose-dependent manner. Utilizing a displacement assay to assess the relative covalent binding of different stilbene and steroidal estrogens with homologous radiolabeled hormones, we found that only indenestrol B exhibited greater ability than diethylstilbestrol (DES) to displace [14C]DES from hepatic microsomal proteins. Except for hydroxypropiophenone and beta-dienestrol, all of the stilbene estrogens studied displaced the radioactive DES binding from these liver proteins to a greater extent than estradiol at comparable concentrations. A marked difference was observed in the ability of alpha- and beta-dienestrol to displace [14C]DES. Using radioinert steroidal estrogens to displace [14C]estradiol, we observed that both estriol and deoxoestrone were significantly less effective in displacing radiolabeled estradiol from liver microsomal proteins. Only ethinyl estradiol and 2-hydroxyestradiol displaced greater than 50% of the radioactive hormone at 1-fold excess concentrations. Interestingly, 11 beta-methoxyethinyl estradiol (Moxestrol) exhibited essentially the same ability to bind liver microsomal proteins as estradiol. When estrone and 2,4-dibromoestradiol were used as substrates together, we found the latter compound to be inactive as a substrate for estrogen hydroxylase (ESH) and additionally inhibited the metabolism of estrone to form the catechol metabolite. Data presented herein suggest that the chemically reactive estrogen metabolites responsible for covalent binding of both stilbene and steroidal estrogens are quinoids derived from catechols formed earlier in metabolism. Except for ethinyl estradiol which is a good substrate for liver, but not kidney microsomal ESH, the carcinogenicity data for the hamster kidney with respect to these estrogens is consistent with the covalent binding data presented.
Carcinogenesis 1987 Feb
PMID:Covalent binding of estrogen metabolites to hamster liver microsomal proteins: inhibition by ascorbic acid and catechol-O-methyl transferase. 380 2

The major objective of this investigation has been to determine the mechanism by which 3-BHA induces forestomach tumours in rodents. In vitro studies of liver microsomal metabolism of [14C]-3-BHA show binding of metabolites to microsomal protein which could be markedly decreased by addition of L-cysteine. p-Toluenesulphonic acid hydrolysis of the labelled microsomes showed a radioactive peak that co-chromatographed with the major product of the reaction of tert-butylquinone (tert-BuQ) and L-cysteine. In vivo binding of metabolites of [14C]-3-BHA to microsomal protein of the forestomach, glandular stomach and liver was determined. Forestomach microsomal protein contained 14 times as much bound radioactivity as glandular stomach and 12 times as much as liver. HPLC studies showed marked qualitative differences in the distribution of labelled compounds in hydrolysates of microsomes from the three tissues. The forestomach contained peaks not present in the other two tissues. In other studies it was shown that the 3-tert-butyl-5-methoxy-1,2-benzoquinone reacted rapidly with NADPH and NADH. tert-BuQ did so more slowly. Current data suggest that two factors may be of importance for 3-BHA carcinogenesis. The first is thiol depletion resulting from direct binding of quinone metabolites of 3-BHA to tissue thiols. Secondary reactions due to the presence of the quinones could also deplete -SH groups. Such thiol depletion could account for the threshold level existing for 3-BHA carcinogenesis. The second factor is an attack on tissue constituents from reactive metabolites of 3-BHA, as is evident from protein binding, and possibly also from oxygen radicals produced as a result of redox cycling of quinone and hydroquinone metabolites of 3-BHA.
 ...
PMID:Studies related to the mechanism of 3-BHA-induced neoplasia of the rat forestomach. 380 16

[4,5,9,10(-3)H]1-nitropyrene was incubated with NADH- or NADPH-fortified rat liver microsomes under an argon atmosphere. Residual substrate and metabolites were extracted with ethyl acetate and analyzed by high pressure liquid chromatography. Both reduced and oxidized products were formed: namely, 1-aminopyrene, trans-4,5-dihydroxy-4,5-dihydro-1-nitropyrene, and 3-, 6- and 8-hydroxy-1-nitropyrene. When incubations were conducted with rat liver cytosol, only the reduced products 1-nitrosopyrene and 1-aminopyrene were detected. In parallel experiments, [4,5, 9,10-3H]1-nitropyrene was administered to rats by intravenous injection or gavage and the bile was collected. After 4 h, approximately one-third of the intravenously-administered compound appeared in the bile as O-glucuronides of 3-, 6- and 8-hydroxy-1-nitropyrene, the O-glucuronide of trans-4,5-dihydroxy-4,5-dihydro-1-nitropyrene, and unidentified glutathione conjugates. The same metabolites were found in rats treated with 1-nitropyrene by gavage; however, only 10% of the dose appeared in the bile within 12 h. These studies indicate that both nitroreduction and ring oxidation are involved in the hepatic metabolism of 1-nitropyrene. The importance of these pathways in the etiology of 1-nitropyrene tumorigenesis is discussed.
Carcinogenesis 1985 Feb
PMID:Comparison of the in vitro and in vivo hepatic metabolism of the carcinogen 1-nitropyrene. 383 67

Nitrosamine-induced hepatocarcinogenesis has been used to investigate the regulation and expression of different drug-metabolizing enzymes in preneoplastic and neoplastic lesions in the female Wistar rat. The enzymes investigated were two phenobarbital-inducible cytochrome P-450 (cyt. P-450) isoenzymes (PB1 and PB2, mol. wt. 52 000 and 53 500, respectively), two 3-methylcholanthrene-inducible forms (MC1 and MC2, mol. wt. 54 500 and 57 000, respectively), NADPH-cytochrome P-450 reductase, the cytosolic glutathione transferases (GSTs) B and C and the microsomal epoxide hydrolase with broad substrate specificity (mEHb). Carcinogen-induced lesions were identified by use of the known markers of hepatocarcinogenesis adenosinetriphosphatase and gamma-glutamyl transpeptidase. While the GSTs and mEHb were increased in all preneoplastic and neoplastic lesions, the levels of the individual cyt. P-450 isoenzymes were characteristically different from each other. In many of the early ATPase deficient islets PB1 was elevated, whereas the content of the other cyt. P-450 forms and NADPH-cytochrome P-450 reductase was either unchanged or slightly lowered. At later stages of hepatocarcinogenesis PB1 returned to the levels of the surrounding tissue, while the other cyt. P-450 isoenzymes were decreased, the most prominent reduction being found in MC1. In neoplastic nodules all the cyt. P-450s and NADPH-cyt. P-450 reductase were diminished, some of them dramatically. These findings indicate that in spite of a common response of groups of P-450s to inducing agents, individual P-450 isoenzymes are also regulated separately. Moreover, the constant elevation of mEHb and GSTs in all lesions investigated in this study demonstrates that these enzymes, which are largely involved in deactivation, are regulated in a different fashion from the predominantly carcinogen-activating monooxygenases. The observed differences in enzyme pattern may provide a useful method for subdividing and categorizing preneoplastic and neoplastic lesions.
Carcinogenesis 1985 Apr
PMID:Regulation and expression of four cytochrome P-450 isoenzymes, NADPH-cytochrome P-450 reductase, the glutathione transferases B and C and microsomal epoxide hydrolase in preneoplastic and neoplastic lesions in rat liver. 392 Dec 70

Histochemical investigation of altered dehydrogenase enzyme activity in putative pre-neoplastic lesions induced by N-ethyl-N-hydroxyethylnitrosamine in the rat liver revealed a clear increase in NADPH-generating potential, most markedly within nodules. Glucose-6-phosphate dehydrogenase, malic enzyme and isocitrate dehydrogenase all showed elevated activity while the activities of succinate dehydrogenase and beta-hydroxybutyrate dehydrogenase were reduced. Alteration in enzyme activity suggested an adaptive shift in metabolism, the increase in levels of enzymes responsible for generation of reduced NADP possibly conferring enhanced drug detoxifying or cholesterogenic potential.
Carcinogenesis 1986 Feb
PMID:Dehydrogenase histochemistry of N-ethyl-N-hydroxyethylnitrosamine-induced focal liver lesions in the rat--increase in NADPH-generating capacity. 394 19

The NADPH-dependent microsomal metabolism of [14C]procarbazine, labeled on the terminal N-methyl group, resulted in the covalent binding of the drug to exogenously added DNA; this reaction was inhibited by metyrapone. Procarbazine metabolism was also shown to result in covalent binding of the methyl group of the drug to microsomal protein upon metabolism, but the extent of protein binding was at least an order of magnitude smaller than that seen with its primary oxidative metabolite. N-isopropyl-alpha-(2-methylazo)-p-toluamide. The characteristics of the reactions leading to the covalent binding of the N-methyl group of the azo derivative to microsomal protein and its metabolism to form the hydrocarbon, methane, possessed a number of similarities in the apparent kinetic parameters (Km and Vmax), induction, and inhibition patterns indicating a common pathway of metabolism to form a reactive intermediate and the involvement of cytochrome P-450. Reduced glutathione stimulated methane formation and inhibited covalent binding to protein. One azoxy derivative, N-isopropyl-alpha-(2-methyl-ONN-azoxy)-p-toluamide, was chemically unstable and its decomposition was shown to lead to covalent binding to microsomal protein. A diazene intermediate and a methyl radical are proposed to be intermediates in the formation of methane during the oxidative metabolism of the azo derivative of procarbazine and a common intermediate in the activation of procarbazine may result in both covalent binding to cellular macromolecules and methane production. In addition, chemical decomposition of the azoxy metabolites may also contribute to a small portion of the covalent binding, but not to methane formation.
Carcinogenesis 1985 Mar
PMID:Metabolic activation of the terminal N-methyl group of N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide hydrochloride (procarbazine). 397 55

The metabolic N-oxidation, N-acetylation and N-deacetylation of the carcinogen benzidine (BZ) and its N-acetylated metabolites were examined in vitro with rat and mouse liver subcellular fractions. N-Oxidation of N-acetylbenzidine (ABZ) and N,N'-diacetylbenzidine (DABZ) was found to occur with NADPH-, NADH-fortified microsomes, although total oxidation at both nitrogens of ABZ was substantially faster than the N-oxidation of DABZ (four times for the mouse and 48 times for the rat). In both species, N-oxidation of ABZ to the arylhydroxylamine, N'-hydroxy-N-acetylbenzidine (N'-OH-ABZ), was somewhat faster than the formation of the arylhydroxamic acid, N-hydroxy-N-acetylbenzidine (N-OH-ABZ). N-Acetylation of BZ and ABZ by liver cytosol was quite efficient for both species (0.7-2.9 nmol/min/mg cytosolic protein), and these rates were found to be 3-10 times faster than their corresponding rates of N-oxidation. N-Deacetylation of ABZ and DABZ by mouse liver microsomes occurred at a rate that was comparable with N-acetylation; while N-deacetylation by rat liver microsomes was relatively slow, only 1-2% of the rate of N-acetylation. In the case of N-hydroxylated derivatives, N-OH-ABZ and N'-OH-ABZ, hepatic cytosolic N-acetylation by both rats and mice to form N-OH-DABZ was quite rapid (0.5-1.9 nmol/min/mg cytosol protein). Hepatic microsomal deacetylation of N-OH-DABZ also occurred with both species and was 2-4 times the rate of N-acetylation. These studies indicate that a significant concentration of potentially electrophilic monoacetylated N-oxidized metabolites may accumulate within the liver cell, and that they may serve as intermediates in the synthesis of the highly toxic metabolite, N-OH-DABZ. A major metabolic pathway for the formation of N-OH-DABZ is proposed as: BZ----ABZ----N'-OH-ABZ----N-OH-DABZ. The activation of N-OH-DABZ by cytosolic N,O-acyltransferase and N'-OH-ABZ by cytosolic sulfotransferase and O-acetyltransferase (acetyl CoA-dependent binding to DNA) were also examined. N-OH-DABZ N,O-acyltransferase and N'-OH-ABZ O-acetyltransferase were found to be significant pathways for rat and mouse liver, respectively. In addition, the DNA adduct formed from N-OH-DABZ in the presence of partially-purified rat hepatic N,O-acyltransferase was shown to be N'-(deoxyguanosin-8-yl)-N-acetylbenzidine, which is identical to that formed in rat liver in vivo and in the direct reaction of N'-OH-ABZ with DNA in vitro under acidic conditions.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1985 Jul
PMID:Hepatic N-oxidation, acetyl-transfer and DNA-binding of the acetylated metabolites of the carcinogen, benzidine. 401 76

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

The mutagenicity patterns and the metabolic behaviour of 4 structurally related ICR compounds were investigated using the Salmonella/microsome test. ICR 191 and ICR 170 reverted 4 his- strains (TA1537 greater than TA100 greater than TA98 and TA1538), while ICR 191-OH and ICR 170-OH reverted TA1537 only, with a narrow range of mutagenic activity. Although all the products tested were shown to contain a common mutagenic impurity, analysis of chemicals fractionated by h.p.l.c. provided evidence that pure ICR 191-OH and ICR 170-OH also induce frameshift errors. The mutagenic activity of all the 4 ICR compounds, as well as of their common impurity, was decreased in the presence of S-9 mix containing rat liver S-9 fractions, a trend confirmed by h.p.l.c. of ICR/S-9 mixtures. Despite the greater mutagenic potency in the absence of metabolic systems, ICR 191 was deactivated far more efficiently and rapidly than ICR 170 by a variety of mouse (liver greater than lung) and rat (liver greater than testis greater than kidney greater than lung greater than striated muscle greater than spleen) S-9 fractions. Mouse preparations were more effective than the corresponding rat preparations. Aroclor 1254 strongly stimulated tha activity of th NADPH-requiring enzymes responsible for ICR deactivation. H.p.l.c. analyses ruled out interconversion among the 4 ICR compounds in the presence of liver S-9 fractions, while revealing the appearance of new distinct peaks for ICR 191, ICR 170 and ICR 170-OH. The selective metabolic deactivation of ICR compounds may be related to the findings of previous carcinogenicity studies (1-3) which showed the induction of lung adenomas following i.v. but not i.p. administration of ICR 170. Conversely, ICR 191 and ICR 191-OH showed no activity even when administered i.v. Since intercalation of ICR compounds into DNA is the molecular basis for both mutagenic and antitumor activities (4), their distinctive metabolic reactivity may be also responsible for the differential efficacy in pharmacological assays.
Carcinogenesis 1982
PMID:Selective deactivation of ICR mutagens as related to their distinctive pulmonary carcinogenicity. 617 36


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