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 conversion of 2-amino-6-methyldipyrido[1,2-a:3' ,2' -d]-imidazole (Glu-P-1), a highly mutagenic principle in a pyrolysate of glutamic acid, to protein-bound metabolites in vitro was examined with microsomes from various tissues of female F344 rats. Addition of NADPH to the incubation mixture containing microsomes and [14C]Glu-P-1 increased the binding of its metabolites to microsomal proteins linearly with time for up to 30 min, while on addition of arachidonic acid the binding increased linearly only for the first 2-4 min of incubation and then levelled off. However, due to the initial rapid binding, addition of arachidonic acid resulted in 6-fold greater binding of metabolites to small intestinal microsomes than addition of NADPH on incubation for 4 min, and with microsomes from liver and colon, arachidonic acid was found to be a better cofactor than NADPH for activation of Glu-P-1. Indomethacin significantly inhibited the increase in binding by arachidonic acid. Additions of linoleic and linolenic acids also increased the binding, but addition of oleic acid had no influence. With hepatic microsomes from 3-methylcholanthrene-treated rats, binding within 4 min after addition of arachidonic acid was greater than that after addition of NADPH and the reverse on further incubation. These findings suggest that prostaglandin synthetase may serve as an alternative enzyme to cytochrome P-450 monooxygenases for conversion of Glu-P-1 to active intermediates in all the rat tissues investigated.
Carcinogenesis 1984 May
PMID:Activation of 2-amino-6-methyldipyrido[1,2-a:3' ,2' -d]imidazole, a mutagenic pyrolysis product of glutamic acid, to bind to microsomal protein by NADPH-dependent and -independent enzyme systems. 642 9

Isoenergetic diets containing 20% corn oil, 20% beef tallow, or an equal mixture of 10% corn oil and 10% beef tallow (mixed fat) were fed to 30 rats per diet for 28 weeks following weaning. DMBA [7,12-dimethylbenz(a)anthracene] was administered (1.75 mg/100 g body weight) in a single oral dose after 4 weeks of feeding. After 28 weeks, 70% of the rats fed corn oil had mammary tumors versus 47% for mixed fat and 30% for tallow. Diet had no effect on the number of tumors per tumor-bearing rat or the proportion of tumors that were adenocarcinomas. Other rats assigned to each of the three diets were killed at the time corresponding to DMBA administration for examination of hepatic mixed-function oxidase activity. NADPH cytochrome c reductase activity and cytochrome P-450 content were higher in rats fed corn oil or mixed fat rather than tallow. However, no significant differences in aryl hydrocarbon hydroxylase, glutathione transferase, and uridine-diphosphoglucuronide transferase activities were observed. The effects of dietary fat saturation on enzyme activity failed to show a clear association with DMBA carcinogenesis. In other rats assigned to the three dietary treatments for 4 or 16 weeks, lipid saturation did not change serum prolactin (PRL) concentrations during diestrus or proestrus. PRL secretion was examined following a provocative stimulus (perphenazine) in rats fed the experimental diets for 4 or 10-22 weeks. Although perphenazine increased serum PRL and depleted the pituitary of PRL, differences in dietary lipid saturation caused no significant changes in these indices. These data show that the incidence of mammary tumors in rats fed high fat diets (20% by weight) was greater in those fed corn oil compared to beef tallow. The effect of dietary lipid source on tumorigenesis was not associated with changes in carcinogen-metabolizing enzyme activity or PRL secretion.
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PMID:Effects of dietary lipid saturation on prolactin secretion, carcinogen metabolism and mammary carcinogenesis in rats. 643 76

The reduction of N-nitrosobis(2-oxopropyl)amine (BOP) and N-nitroso(2-oxopropyl)propylamine (NOPPA) by hepatic and pancreatic cytosol and microsomes from Syrian golden hamsters and Sprague-Dawley rats has been examined. All hepatic fractions reduced both substrates, although the activity depended on the fraction tested and the cofactor employed (NADH or NADPH). Generally, hamster hepatic fractions contained higher activity than the rat hepatic fractions and BOP was a better substrate than NOPPA. Of the pancreatic fractions, only cytosol exhibited reductase activity. The hamster cytosol was able to utilise both cofactors, but the rat fraction exhibited activity only when NADPH was present. BOP was the better substrate for the pancreatic enzymes and in the presence of NADPH, the rat and hamster activities were about equal. These results suggest that the pancreatic reduction of BOP to HPOP is unlikely to be a significant factor in the species-specific induction of pancreatic cancer by BOP.
Carcinogenesis 1983 Nov
PMID:Enzymatic reduction of beta-ketonitrosamines. 664 Aug 48

1,2-Dichloroethane, 1,1,1-trichloroethane and 1,1,2,2-tetrachloroethane appear to be metabolized by hepatic nuclear cytochrome P-450. All of these compounds are converted to chlorinated metabolites after incubation with hepatic nuclei and an NADPH-generating system plus EDTA, with the omission of any component eliminating metabolite production. In addition, CO, an inhibitor of cytochrome P-450, diminished the production of the chlorinated metabolites by hepatic nuclear preparations. The major metabolites of the chlorinated ethanes from hepatic microsomal cytochrome P-450, viz. chloroacetaldehyde from 1,2-dichloroethane, 2,2,2-trichloroethanol from 1,1,1-trichloroethane, and dichloroacetic acid from 1,1,2,2-tetrachloroethane, were also produced from the three chloroalkanes by hepatic nuclear cytochrome P-450. The levels of the metabolites produced were 65, 0.09 and 4.4 nmol/nmol cytochrome P-450/60 min. It is proposed that the pathways for the formation of these metabolites by hepatic nuclear cytochrome P-450 are as for their production by hepatic microsomal cytochrome P-450. Chloral hydrate was produced from 1,1,1-trichloroethane by hepatic nuclei plus NADPH, but not by hepatic microsomes. The presence of reactive species or transient enzyme bound intermediates in the pathways for the cytochrome P-450 dependent metabolism of the chloroethanes in hepatic nuclei is suggested by the observation that nuclear cytochrome P-450 is degraded in the presence of the chloroethanes in a NADPH dependent process which is inhibited by CO. It is proposed that, although the cytochrome P-450 dependent metabolism of the chloroethanes in microsomes can greatly exceed that in nuclei, the metabolism of 1,2-dichloroethane and 1,1,2,2-tetrachloroethane by nuclear cytochrome P-450 may in part mediate the mutagenicity and carcinogenicity of parent compounds.
Carcinogenesis 1984 May
PMID:Metabolism of chloroethanes by rat liver nuclear cytochrome P-450. 672 74

The biochemical denitrosation of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in tissues from four strains of rat, inbred Buffalo, Lewis, B-N, and the random-bred Sprague-Dawley, with different sensitivities to MNNG-induced gastric carcinomas was investigated as a possible explanation for the species/strain differences in MNNG-induced carcinogenesis. An analytical HPLC method was developed to assay denitrosation of MNNG to N-methyl-N'-nitroguanidine (MNG) by cytosolic, microsomal, mitochondrial, and nuclear cell fractions. All the activity was contained in the microsomal and cytosolic fractions, with the major portion occurring in the cytosol. The activity in both fractions was NADPH-dependent, but denitrosation was not reduced by inhibitors of the cytochrome P-450 system. Denitrosation of MNNG post-mitochondrial supernatant (S9) fractions from liver, glandular stomach mucosa, and duodenal mucosa of the four rat strains was determined. In all strains, denitrosation activities were highest in liver. Comparisons between the three strains most sensitive to MNNG-induced gastric carcinogenesis indicated no large differences for any tissue. However, Buffalo, the most resistant strain, did have a higher level of denitrosating activity in all three tissues, which is consistent with the hypothesis that higher levels of detoxifying enzymes may lead to a decreased incidence of tumors. On the other hand, denitrosation accounts for less than 3% of the MNNG that disappears during the incubation period so that the relevance of denitrosation as a mechanism in strain-specific sensitivity to MNNG-induced gastric carcinoma requires additional studies.
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PMID:Biochemical mechanisms on species differences in gastric carcinogenesis. 674 4

Incubation of hepatocarcinogenic aminoazo dye, o-aminoazotoluene (OAT) with rat liver microsomes together with NADPH and NADH yielded N-hydroxy-OAT (I), 4'-hydroxy-OAT (II) and a smaller amount of 2'-hydroxymethyl-3-methyl-4-aminoazobenzene (III). As an artifact 4,4'-bis(o-tolylazo)-2,2' -dimethylazoxybenzene (IV) was also detected in a small quantity. The mutagenicities of these metabolites were assayed by using Salmonella typhimurium TA98 and TA100 together with S-9 prepared from the livers of rats treated with polychlorinated biphenyl mixture (PCB). OAT and III were strongly mutagenic, but only when S-9 was present. In contrast, I was a strong mutagen regardless of the presence or absence of S-9. II and IV were non-mutagenic. The yields of I, II and III from OAT were pronouncedly reduced by addition of cytochrome P-450 inhibitors, especially by a cytochrome P-448 inhibitor 7,8-benzoflavone. Mutagenesis by OAT was also inhibited by addition of 7,8-benzoflavone. Activation of OAT for mutagenesis was enhanced by pretreatment of the donor rats with PCB or 3-methyl-cholanthrene and to a much lesser extent by phenobarbital. These findings suggest that N-hydroxylation of OAT mainly proceeds via catalysis by cytochrome P-448 and that this process is an obligatory step for the activation of OAT. Synthetic methods for the preparation of new azo compounds such as I, IV and 2',3-dimethyl-4-nitrosoazobenzene are described.
Carcinogenesis 1982
PMID:In vitro metabolism of o-aminoazotoluene and mutagenesis of Salmonella by the metabolites. 675 67

The role of mammalian metabolizing enzymes in the bioactivation of promutagenic factors present in synthetic indigo has been studied in Salmonella typhimurium TA98. The activation process appears to be NADPH dependent and the enzymes involved are localized in the microsomes. Comparison of the three types of induction of rat liver homogenate showed that 3-methylcholanthrene is the most effective. Furthermore, this study revealed that 1,1'-azobis (N,N-dimethylformamide) not only oxidizes glutathione but also inhibits those microsomal enzymes that are involved in the bioactivation process.
Carcinogenesis 1982
PMID:Metabolic activation of promutagenic factors in synthetic indigo by mammalian microsomes. 675 76

The enzyme NADPH-cytochrome c (P-450) reductase was identified by indirect immunofluorescence in hepatocytes, bronchioles, and proximal tubules of liver, lung, and kidney, respectively, of rats and minipigs that had been injected with phenobarbital or saline. The distribution of this component of the cytochrome P-450-mediated microsomal system may be relevant to sites of drug toxicity and carcinogenesis.
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PMID:Immunofluorescence of NADPH-cytochrome c (P-450) reductase in rat and minipig tissues injected with phenobarbital. 677 Apr 64

The mutagenic activities of trans-7,8-dihydro-7,8-dihydroxybenzo[a]-pyrene (BP 7,8-diol) and of trans-3,4-dihydroxy-7,12-dimethylbenz[a]-anthracene (DMBA 3,4-diol) towards S. typhimurium TA100 were measured in assays that were carried out on a micro-scale in liquid medium in the presence of microsomal fractions prepared from mouse skin or rat liver. In the presence of an NADPH-generating system, microsomal enzymes converted both diols into mutagens that were probably the respective 'bay-region' diol-epoxides. The rate of the enzyme-catalysed conversion of the BP 7,8-diol into mutagens by microsomal preparations from mouse epidermis was similar to that occurring with microsomes from rat liver. Pretreatment of mice by the topical application of benz[a]anthracene (BA) or 7,12-dimethylbenz[a]-anthracene (DMBA) increased the mutagenic activity of BP 7,8-diol mediated by mouse skin microsomal preparations by 2-fold and this was paralleled by a 4-fold increase in epidermal aryl hydrocarbon (benzo[a]pyrene) hydroxylase (AHH) activity. The results are discussed in relation to the high susceptibility of mouse skin to polycyclic aromatic hydrocarbon (PAH) carcinogenesis.
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PMID:Mutagenicity of benzo[a]pyrene 7,8-dihydrodiol and 7,12-dimethylbenz[a]anthracene 3,4-dihydrodiol in S. typhimurium mediated by microsomes from rat liver and mouse skin. 677 25

Nitrite was formed on incubation of N-nitrosamines with a reconstituted monooxygenase system, consisting of cytochrome P-450 (P-450) and NADPH P-450 reductase from pig liver. Nitrite was not obtained when the nitrosamines were incubated with NADPH P-450 reductase alone or when molecular oxygen or NADPH were omitted. Interaction of nitrosamines with the reconstituted P-450 system or with hemoglobin under reducing conditions resulted in optical spectra identical with those obtained with nitrite. It is proposed that N-nitrosamines are denitrosated by electron transfer from the hemoprotein iron to the nitrosamine molecule.
Carcinogenesis 1982
PMID:Metabolic nitrite formation from N-nitrosamines: evidence for a cytochrome P-450 dependent reaction. 680 75


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