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

The metabolism of chemical carcinogens was investigated in liver preparations from 28 captive woodchucks (Marmota monax). Of these, 23 were naturally infected with the woodchuck hepatitis virus (WHV), and eight also had primary hepatocellular carcinoma (PHC). Twenty-nine parameters were investigated in liver subcellular fractions, including cross-reactivity with HBsAg, and biochemical parameters, such as gamma-glutamyl transpeptidase, cytochrome P-450 and microsomal monooxygenases (aryl hydrocarbon hydroxylase, ethoxycoumarin and ethoxyresorufin deethylases, aminopyrine and dimethylnitrosamine demethylases, and testosterone 7 alpha-, 16 alpha- and 6 beta-hydroxylases), uridine 5'-diphosphoglucuronosyl transferase, GSH and related enzymes (peroxidase, reductase and S-transferase), as well as other cytosolic enzyme activities (glucose 6-phosphate and 6-phosphogluconate dehydrogenases, NADPH- and NADH-dependent diaphorases, and DT diaphorase). In addition, liver preparations were used in order to quantify the metabolic activation into bacterial mutagens of five procarcinogens (aflatoxin B1, the pyrolysis products Trp-P-2 and MeIQ, 2-aminofluorene and dimethylnitrosamine) and the decrease of potency of three direct-acting mutagens (sodium dichromate, ICR 191 and 4-nitroquinoline 1-oxide). WHV infection produced a significant stimulation of carcinogen metabolism, as shown by the simultaneous change in detoxification parameters (GSH depletion) and activation indices (enhancement of microsomal monooxygenases and of procarcinogen activation into mutagenic metabolites). There were no significant differences between WHV-positive samples from animals without PHC and the noncancerous tissue of PHC-bearing animals, whereas a decrease of both activation and detoxification indices was recorded in the tumorous tissue. There was a considerable interindividual variability among WHV carriers, which was tentatively ascribed to genetic factors. Pregnancy was the only known factor influencing the results in WHV carriers. However, even by excluding pregnant animals, the effects on carcinogen metabolism produced by WHV infection were still statistically significant. These results, together with previous data obtained in humans, revealed that metabolic factors may play a role in the synergism between viral hepatitis and chemical hepatocarcinogens in the etiopathogenesis of PHC.
Carcinogenesis 1989 Jun
PMID:Enhanced metabolic activation of chemical hepatocarcinogens in woodchucks infected with hepatitis B virus. 272 Sep 3

Cytochrome P-450-mediated redox cycling between the synthetic estrogen diethylstilbestrol (DES) and diethylstilbestrol-4',4"-quinone (DES Q) has previously been demonstrated. Cytochrome P-450 reductase catalyzes the reduction of DES Q presumably via a semiquinone formed by one-electron reduction. A reducing action of NAD(P)H quinone reductase (EC 1.6.99.2) mediating two-electron reduction of DES Q has been investigated in the present work. Quinone reductase catalyzed the conversion in the presence of NADH or NADPH of DES Q to 53-65% Z-DES, a marker product of reduction. Dicumarol (15 microM), a known specific inhibitor of quinone reductase, inhibited this reduction almost completely. Using microsomes from Syrian hamster kidney, a target organ of estrogen-induced carcinogenesis, the reduction of DES Q was only partially inhibited by dicumarol. Apparent Km values of quinone reductase and cytochrome P-450 reductase were 17.25 and 11.9 microM, respectively. These data demonstrate that in hamster kidney, quinone reductase and cytochrome P-450 reductase compete for the reduction of DES Q. Microsomal 02-. radical generation was stimulated 10-fold over base levels by the addition of 100 microM DES Q. The formation of 02-. radicals was inhibited by addition of superoxide dismutase (0.2 mg/ml) or by 2'-AMP or NADP, known inhibitors of cytochrome P-450 reductase. In contrast, dicumarol enhanced microsome-mediated 02-. formation. It is concluded that cytochrome P-450 reductase in hamster kidney microsomes mediates one-electron reduction of estrogen quinones to free radicals (semiquinones), which may subsequently enter redox cycling with molecular oxygen to form 02-.. Moreover, quinone reductase reduces DES Q directly to E- and Z-DES, and thus may prevent the formation of toxic intermediates during redox cycling of estrogens. Measurements of quinone reductase activity in liver and kidney of hamsters treated with estrogen for various lengths of time revealed a temporary decrease in activity by 80% specifically in the kidney after 1 month of chronic treatment with estradiol. Thus, a temporary decrease in quinone reductase activity, which occurred specifically in estrogen-exposed hamster kidney, may enhance the formation of free radical intermediates generated during biotransformation of estrogens.
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PMID:Temporary decrease in renal quinone reductase activity induced by chronic administration of estradiol to male Syrian hamsters. Increased superoxide formation by redox cycling of estrogen. 283 Nov 97

Three isomeric quinone metabolites of the environmental carcinogen benzo[a]pyrene undergo reversible, univalent oxidation-reduction cycles involving the corresponding benzo[a]pyrene diols and intermediate semiquinone radicals. Under anaerobic conditions, benzo[a]pyrene 1,6-dione, benzo[a]pyrene 3,6-dione, and benzo[a]pyrene 6,12-dione are readily reduced by mild biological agents such as NADH and glutathione. The benzo[a]pyrene diols, in turn, are very rapidly autooxidized to diones when exposed to air. Substantial amounts of hydrogen peroxide are produced during these autooxidations. The benzo[a]pyrene diol/benzo[a]pyrene dione interconversions proceed by one-electron steps; the corresponding semiquinone radicals were detected as intermediates when the reactions were carried out at high pH. Benzo[a]pyrene diones are electron-acceptor substrates for NADH dehydrogenase. Catalytic amounts of these metabolites, together with this respiratory enzyme, function as cyclic oxidation-reduction couples to link NADH and molecular oxygen in the continuous production of hydrogen peroxide. Benzo[a]pyrene diones induce strand scissions when incubated with T7 DNA. The damage is modified by conditions that indicate that reduced oxygen species propagate the reactions responsible for strand scission. Benzo[a]pyrene diones are cytotoxic at low concentrations to cultured hamster cells. The cytotoxic effect can be substantially reduced by depletion of oxygen from the growth medium and the atmosphere in which the cells are incubated. The results support the hypothesis that the biological activity of benzo[a]pyrene diones is due to the regenerative oxidation-reduction cycles involving quinone and hydroquinone forms; activated oxygen species and semiquinone radicals formed during these cycles are most likely responsible for the observed cytotoxic action. The role of activated oxygen species in carcinogenesis is discussed.
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PMID:Benzo[a]pyrene dione-benzo[a]pyrene diol oxidation-reduction couples; involvement in DNA damage, cellular toxicity, and carcinogenesis. 300 1

Several endogenous cellular constituents were tested for their ability to produce superoxide anion (O2-) from ground-state molecular oxygen upon irradiation by solar radiation. The pyridine cofactors NADPH and NADH, riboflavin, and the nucleosides 2-thiouracil and 4-thiouridine were found to sensitize the transmission of photon energy from solar radiation and monochromatic radiation (290, 334, 365, and 405 nm) to oxygen, resulting in O2- formation, as detected by superoxide dismutase-inhibitable cytochrome c reduction. Quantum yields for the production of O2- indicate that NADPH is the most efficient and riboflavin the least efficient of the compounds tested. These data indicate that endogenous compounds may participate in the production of O2- by solar radiation and imply that O2- may play a role in sunlight-induced erythema and dermal carcinogenesis.
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PMID:Superoxide anion is generated from cellular metabolites by solar radiation and its components. 301 63

The metabolism of N-butyl-N-(3-formylpropyl)nitrosamine, a presumptive intermediate metabolite of the urinary bladder carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine, by rat liver has been examined. N-Butyl-N-(3-formylpropyl)nitrosamine was metabolized by an NADH-dependent reduction to N-butyl-N-(4-hydroxybutyl)nitrosamine and by an NAD+-dependent oxidation to N-butyl-N-(3-carboxypropyl)nitrosamine. The reduction of N-butyl-N-(3-formylpropyl)nitrosamine was inhibited by pyrazole. The oxidation of N-butyl-N-(3-formylpropyl)nitrosamine was studied further. The rate of oxidation in total rat liver was 3 mumol/min/g liver or 21 nmol/min/mg protein and was similar to that found for the oxidation of propionaldehyde, a model substrate for isozymes of rat liver aldehyde dehydrogenase. The rate of oxidation of N-butyl-N-(3-formylpropyl)nitrosamine by isozymes in rat liver cytosol was 2-2.5 times that found for propionaldehyde. The apparent Km for the NAD+-dependent oxidation of N-butyl-N-(3-formylpropyl)nitrosamine was 20-30 microM, which is considerably lower than values reported for known substrates of aldehyde dehydrogenase. The NAD+-dependent oxidation of N-butyl-N-(3-formylpropyl)nitrosamine was inhibited 40-50% by 50 microM disulfiram, 60-70% by 100 microM disulfiram, and 50% by 0.4 mM sodium arsenite. These studies show that N-butyl-N-(3-formylpropyl)nitrosamine is very rapidly oxidized to N-butyl-N-(3-carboxypropyl)nitrosamine in rat liver by aldehyde dehydrogenase and the results may help to explain why the 3-formylpropyl intermediate has not been directly identified as a metabolite of N-butyl-N-(4-hydroxybutyl)nitrosamine in urine or in isolated hepatocytes.
Carcinogenesis 1988 Nov
PMID:Oxidation of N-butyl-N-(3-formylpropyl)nitrosamine to N-butyl-N-(3-carboxypropyl)nitrosamine in rat liver and inhibition by disulfiram. 318 Mar 45

1-Nitropyrene, the predominant nitropolycyclic aromatic hydrocarbon found in diesel exhaust, is a mutagen and tumorigen. 1,6-Dinitropyrene is present in diesel exhaust in much smaller quantities than 1-nitropyrene, but is much more mutagenic and carcinogenic. In an attempt to understand this difference in biological potencies, we have compared the extent of DNA binding by these two nitropyrenes in vivo. We have also determined the effect of 1-nitropyrene pretreatment upon the induction of nitroreductases and the subsequent DNA binding by both 1-nitropyrene and 1,6-dinitropyrene. Covalent DNA binding by 1-nitropyrene could not be detected in vivo; however, 1,6-dinitropyrene formed N-(deoxyguanosin-8-yl)-1-amino-6-nitropyrene as the major DNA adduct in rat liver, kidney, urinary bladder and mammary gland, with the highest levels being found in the bladder. The capability of liver microsomes to catalyze the oxidative metabolism of 1-nitropyrene was unchanged after treating rats with 8 mg/kg 1-nitropyrene. Cytochrome P-450, NADPH-cytochrome P-450 reductase and cytochrome b5 levels were also unchanged, while slight increases were detected in NADH-cytochrome b5 reductase and epoxide hydrase activities. Liver cytosolic and microsomal nitroreductase activities toward both 1-nitropyrene and 1,6-dinitropyrene were increased 2-fold, and cytosolic nitrosoreductase activity toward 1-nitrosopyrene and 1-nitro-6-nitrosopyrene was elevated by approximately 20%. DNA binding of both 1-nitropyrene and 1,6-dinitropyrene in vitro was 2-fold higher when using cytosol from 1-nitropyrene-pretreated rats. However, pretreatment of rats with 1-nitropyrene only slightly increased the amount of in vivo DNA binding by 1,6-dinitropyrene except in kidney where there was a 60% increase. These results indicate that although nitroreduction is involved in DNA adduct formation by 1,6-dinitropyrene, additional factors (e.g. O-acetylation) limit the extent of DNA binding in vivo.
Carcinogenesis 1988 Mar
PMID:DNA binding by 1-nitropyrene and 1,6-dinitropyrene in vitro and in vivo: effects of nitroreductase induction. 334 77

The metabolism of the carcinogenic nitrosamine, N'-nitrosonornicotine (NNN), to reactive intermediates which bind covalently was assessed using male Sprague-Dawley rat liver microsomes. The NADPH-dependent covalent binding of [14C]NNN was linear with time up to 90 min and protein concentration up to 3.0 mg/ml. The apparent Km and Vmax of the binding were determined from the initial velocities and found to be 0.91 mM and 4.7 pmol/min/mg protein, respectively. Although NNN is not a hepatocarcinogen, this amount of NADPH-dependent covalent binding is 7-fold greater than that reported for dimethylnitrosamine, a potent hepatocarcinogen. Extensive covalent binding of [14C]NNN to liver and muscle microsomal protein was also present in the absence of an NADPH-generating system and in the presence of 50% methanol, indicating a non-enzymatically mediated reaction. Addition of the nucleophiles glutathione, cysteine and N-acetylcysteine significantly decreased (p less than 0.01) the non-NADPH-dependent binding, but did not affect NADPH-dependent binding. In vitro addition of the cytochrome P-450 inhibitors metyrapone, piperonyl butoxide and SKF-525A significantly decreased (p less than 0.05) NADPH-dependent binding of [14C]NNN by 27-40%. NADH did not replace NADPH in supporting covalent binding. Replacement of an air atmosphere with nitrogen or CO:O2 (8:2) significantly decreased (p less than 0.05) NADPH-dependent binding of [14C]NNN by 40 and 27%, respectively. Aroclor 1254 pre-treatment of the rats did not enhance the NADPH-dependent binding of [14C]NNN. These data indicate that cytochrome P-450 is at least in part responsible for the metabolic activation of the carcinogen NNN but also suggest additional mechanisms of activation.
Carcinogenesis 1986 Jan
PMID:Characterization of covalent binding of N'-nitrosonornicotine in rat liver microsomes. 351 Jul 49

Xanthine oxidase catalyzed mutagenicity of 4-nitrobiphenyl (NBP), a dog-bladder carcinogen, was tested in Ames assay using Salmonella typhimurium TA98 strains. NBP was active as a mutagen in the parent strain TA98 which is proficient in nitroreductase, while it was inactive in the strain TA98NR which is deficient in nitroreductase. However, preincubation of NBP at 37 degrees C with NADH and commercial preparations of xanthine oxidase for 30 min resulted in a dose-dependent increase in the mutagenic activity in TA98NR. Allopurinol blocked the xanthine oxidase catalyzed mutagenicity of NBP in TA98NR and the extent of inhibition was dependent upon the concentration of the inhibitor. Rat-liver and dog-bladder cytosol preparations also enhanced the mutagenic activity of NBP in TA98NR in a dose-dependent manner. In addition, the cytosol-mediated activity was also inhibited by allopurinol, implying that the cytosolic enzyme activity might be due to xanthine oxidase. In vitro enzymatic reduction of NBP using bacterial cell lysates of TA98 and TA98NR revealed the major product of reduction to be 4-aminobiphenyl. The transient intermediates of reduction were not detected during the in vitro incubation. The reduction intermediate N-hydroxylaminobiphenyl showed direct and equal mutagenic activity in both TA98 and TA98NR, in contrast to NBP. These results suggest that N-hydroxylaminobiphenyl is generated during the preincubation of NBP with xanthine oxidase or cytosolic preparations and the former might account for the mutagenicity of NBP. Furthermore, the occurrence of such enzyme(s) in the target tissue for NBP carcinogenesis, support the hypothesis that metabolic activation of the bladder carcinogen NBP could occur within the target organ by virtue of its intrinsic metabolic potential.
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PMID:Xanthine oxidase-mediated mutagenicity of the bladder carcinogen 4-nitrobiphenyl. 353 36

In the present study the role of two families of cytochrome P-450 proteins and the contribution of the cytosolic fraction in the activation of N-nitrosopiperidine to mutagens in the Ames test were investigated. The bioactivation of this nitrosamine was preferentially catalysed by the phenobarbitone-induced cytochromes P-450, in contrast to the 3-methylcholanthrene-induced cytochromes P-448. The mutagenicity of nitrosopiperidine catalysed by microsomes, in the absence of cytosol, was lower when compared with that observed with S9 fractions. Cytosol itself could not activate nitrosopiperidine but potentiated the microsome-mediated mutagenicity of the carcinogen. The cytosolic potentiation was still evident when microsomal metabolism was terminated, indicating that cytosolic enzyme(s) can further convert the microsome-generated metabolites to more potent mutagens. The cytosolic enzyme(s) was inducible by prior treatment of the rats with phenobarbitone or Arochlor 1254 but not 3-methylcholanthrene. The microsome-mediated activation of nitrosopiperidine could be supported by NADH in the absence of NADPH. It is therefore concluded that the activation of nitrosopiperidine to mutagen(s) involves, in addition to NADH- and NADPH-dependent microsomal enzymes, cytosolic proteins.
Carcinogenesis 1987 Nov
PMID:Bioactivation of N-nitrosopiperidine to mutagens: role of hepatic cytochrome P-450 proteins and contribution of cytosolic fraction. 366 60

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


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