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 cyclopento[c,d]pyrene (CPP) to forms which are mutagenic to Salmonella typhimurium strain TA98 has been demonstrated in systems which generate peroxyl radicals. The systems examined included prostaglandin H synthase (PHS) and arachidonic acid, 15-hydroperoxy-5,8,11,13-eicosatetraenoic acid (15-HPETE) and hematin, and the autoxidation of the sulfite ion. In all cases concentration-dependent activation of CPP was observed at hydrocarbon concentrations between 10 and 100 microM. Neither CPP nor the peroxyl radical systems alone were mutagenic or toxic to the tester strain. The use of hydroxygen peroxide with PHS, a peroxidative system which does not yield peroxyl radicals, does not activate CPP. The involvement of a CPP epoxide was examined using 1,1,1-trichloropropene-2,3-oxide. Addition of this epoxide hydrolase inhibitor to incubations of CPP with the PHS/arachidonic acid system resulted in a 210% increase in induced revertants relative to the system in the absence of the inhibitor. The addition of pure rat liver microsomal epoxide hydrolase to incubations of CPP with the 15-HPETE/hematin system resulted in a concentration-dependent loss of mutagenicity, further supporting the intermediacy of an epoxide. The site of metabolism of CPP is the cyclopenteno double bond based on the formation of products which display distinct pyrene-type fluorescence spectra. The involvement of the cyclopenteno double bond also is shown by the inability of the 15-HPETE/hematin system to activate 3,4-dihydrocyclopenteno[c,d]pyrene as a mutagen. CPP is the first environmentally-relevant carcinogenic hydrocarbon found to be activated directly by peroxyl radical systems without prior biotransformation to a diol derivative by the cytochrome P-450 system. These findings expand the range of potentially toxic substrates to be considered for activation by peroxyl radical pathways.
Carcinogenesis 1988 Dec
PMID:Metabolic activation of cyclopenteno[c,d]pyrene by peroxyl radicals. 319 75

Aerobic metabolism of 1-nitrobenzo[e]pyrene (1-nitro-BeP) by rat liver microsomes produced 1-nitro-BeP trans-4,5-dihydrodiol, 6-hydroxy-1-nitro-BeP, and 8-hydroxy-1-nitro-BeP. When 3,3,3-trichloropropylene 1,2-oxide was incorporated into the metabolism, 1-nitro-BeP 4,5-oxide was the predominant metabolite, and 1-nitro-BeP trans-4,5-dihydrodiol was not detected. All of the metabolites were purified by both reversed- and normal-phase HPLC and characterized by analysis of their mass and 500 MHz proton NMR spectral data. 1-Nitro-BeP was not metabolized under hypoxic conditions. 1-Nitro-BeP and its four metabolites were assayed in Salmonella typhimurium tester strains TA98, TA98NR and TA98/1,8-DNP6, both in the presence and absence of S9 activation. As predicted, 1-nitro-BeP was a weak mutagen without S9 (2 revertants/micrograms in TA98); the addition of S9 resulted in approximately 18, 17 and 4 revertants/micrograms in TA98, TA98NR and TA98/1,8-DNP6 respectively. The two phenolic metabolites were mutagenic both in the presence and absence of S9, producing moderate responses (19-84 revertants/micrograms). In addition, while the 1-nitro-BeP 4,5-oxide was only weakly mutagenic in TA98 (6-14 revertants/micrograms), 1-nitro-BeP trans-4,5-dihydrodiol was unexpectedly potent (approximately 300 revertants/micrograms both with and without S9). These results indicate that microsomal epoxidation of 1-nitro-BeP followed by epoxide hydrolase-catalyzed hydrolysis of the resulting epoxide to the 1-nitro-BeP trans-4,5-dihydrodiol results in the most potent mutagenic derivatives. The weak mutagenicity of 1-nitro-BeP 4,5-oxide demonstrates that not all epoxides of nitrated polycyclic aromatic hydrocarbons (PAHs) are more mutagenic than the corresponding parent nitro-PAHs. Also, the lower S9-mediated mutagenicity of 1-nitro-BeP in TA98/1,8-DNP6 compared with TA98 indicates that the mutagenicity of 1-nitro-BeP is dependent upon nitroreduction and transesterification. Finally, we previously hypothesized that nitrated PAHs with their nitro substituents perpendicular or nearly perpendicular to the aromatic rings are very weak or nondirect-acting mutagens in Salmonella typhimurium tester strains. The results reported in this communication demonstrate that ring-oxidized derivatives of nitro-PAHs do not always follow this structure--mutagenicity correlation.
Carcinogenesis 1988 Jun
PMID:Microsomal metabolism of 1-nitrobenzo[e]pyrene to a highly mutagenic K-region dihydrodiol. 328 32

Incubation of r-1,t-2-dihydroxy-t-3,4-oxy-1,2,3,4-tetrahydrochrysene (anti-chrysene-1,2-diol 3,4-oxide), the bay-region diol-epoxide of chrysene, with rat liver microsomes in the presence of NADP+ and DNA, followed by 32P-postlabelling analysis of the DNA, revealed the presence of at least two adducts not detected when anti-chrysene-1,2-diol 3,4-oxide was incubated with DNA alone. The formation of these adducts was not blocked by the epoxide hydrolase inhibitor 1,1,1-trichloropropane-2,3-oxide. One of the adducts cochromatographed with the adduct spot obtained when authentic 9-hydroxy-r-1,t-2-dihydroxy-t-3,4-oxy-1,2,3,4-tetrahydrochrysene (anti-9-OH-chrysene-1,2-diol 3,4-oxide) was reacted with DNA. Evidence suggested that a second adduct could also be formed by further metabolism of anti-9-OH-chrysene-1,2-diol 3,4-oxide. In addition, evidence was obtained for the further metabolism of the syn-isomer of chrysene 1,2-diol 3,4-oxide and the anti-isomer of a non-bay-region diol-epoxide of dibenz[a,c]anthracene to DNA binding species, but not for that of either the anti- or syn-isomers of the bay-region diol-epoxide of benzo[a]pyrene, the anti-isomers of the bay-region or a non-bay-region diol-epoxide of benz[a]anthracene, or the anti-isomer of the bay-region diol-epoxide of benzo[b]fluoranthene.
Carcinogenesis 1988 May
PMID:Further metabolism of diol-epoxides of chrysene and dibenz[a,c]anthracene to DNA binding species as evidenced by 32P-postlabelling analysis. 336 49

The effect of carcinogenesis on various hepatic microsomal parameters and related cell functions was studied in two tumor models. Hepatocarcinoma was produced by diethylnitrosamine (DEN) and 2-acetylaminofluorene (2-AAF) (Solt-Farber model) and mammary adenocarcinoma using R3230 AC cancer cell line. In these models the effect of the tumor on metabolic functions of hepatocytes was studied. In the DEN/2AAF tumor model in nodules phase I components (cytochrome P-450, aminopyrine N-demethylase, arylhydrocarbon hydroxylase) were reduced, together with microsomal progesterone content and total and specific progesterone binding. Phase II components (glutathione, glutathione S-acyltransferase, UDP-glucuronyl transferase, epoxide hydrolase) were increased. In hepatoma the effects were more enhanced. Nodules grown in the speen retained the dedifferentiated enzyme characteristics. In the R3230 AC mammary adenocarcinoma phase I components of the hepatic endoplasmic reticulum were reduced, and phase II components increased. Progesterone content and receptor binding were also increased. These results indicate that enzymatic abnormalities in the liver cell are connected with cancer production and the hepatic dedifferentiation seems to be indistinguishable in tumor-bearing liver from those seen with extrahepatic neoplasms.
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PMID:Hepatic metabolism and carcinogenesis. Its role in hepatoma and adenocarcinoma. 338 80

The effects of a series of barbiturates, of known and varying liver tumor-promoting ability, on several short-term endpoints including liver weight and liver-to-body weight ratio increases and induction of cytochromes(s) P-450 and epoxide hydrolase activities were examined. Male F344 rats (3 months of age) were administered barbiturates in the drinking water for 12 days. At the end of the treatment period they were killed, body and liver weights were taken, microsomal p-nitroanisole O-demethylation and epoxide hydration, and liver S-9 O-dealkylation of ethoxy-, pentoxy- and benzyloxyresorufin were measured. The latter two substrates have been shown to be preferentially metabolized by the major phenobarbital-inducible form of cytochrome(s) P-450 (P-450b), and were employed since they offered a means of differentiating more clearly varying levels of P-450 induction. Exposure to sodium barbital (SB) and sodium phenobarbital (PB) resulted in significant increases in liver weight and liver-to-body weight ratios. Induction of cytochrome(s) P-450 and epoxide hydrolase activities by the various barbiturates depended on the functional groups on C5. When ranked in terms of decreasing induction potency, the following order was obtained for each enzyme activity quantitated: PB, SB, sodium pentobarbital, amobarbital, hexobarbital and the C5-unsubstituted parent compound (barbituric acid). Thus, the barbiturates were found to exhibit a spectrum of induction potencies, with PB and SB, the most potent liver tumor promoters, yielding the greatest degree of liver weight increase and induction of cytochrome(s) P-450 and epoxide hydrolase activities.
Carcinogenesis 1987 Jan
PMID:Induction of alkoxyresorufin O-dealkylases, epoxide hydrolase, and liver weight gain: correlation with liver tumor-promoting potential in a series of barbiturates. 349 11

Heterogenous rabbit antisera were prepared against microsomal proteins of hyperplastic hepatic nodules (HPN) induced by chemicals, and were utilized to assess the antigenic differences of microsomal polypeptides within a normal liver, HPN, and hepatocellular carcinomas (HCC), utilizing immunodetection of antigens separated electrophoretically and transferred to nitrocellulose. Although most antigens were common to all microsomes, differences (increase or decrease) were noted in some polypeptides not only between the normal liver and HPN, but also between HPN and HCC. On the other hand, monoclonal antibodies against epoxide hydrolase (EH), which was initially found as the PN antigen, reacted to a single polypeptide with a molecular weight of 49,000 in all the microsomes. These results suggested that there is little molecular modification of EH during hepatic carcinogenesis.
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PMID:Immunochemical studies of microsomal membranes of rat preneoplastic and neoplastic hepatocytes. 357 76

Our recent studies have shown that ellagic acid, a naturally occurring dietary plant phenol, protects BALB/c mice against 3-methylcholanthrene-induced skin tumorigenesis. To further elucidate the mechanism of the antineoplastic action of ellagic acid its effect on hepatic and pulmonary benzo[a]pyrene (BP) metabolism, cytochrome P-450-dependent monooxygenases and glutathione S-transferase activities were studied in BALB/c mice. Chronic oral feeding of the compound in drinking water (0.3 mg/l for 16 weeks) or acute intraperitoneal administration (50 mg/kg for five consecutive days) of ellagic acid resulted in 20-25% decreases in hepatic and pulmonary cytochrome P-450 levels. Hepatic and pulmonary aryl hydrocarbon hydroxylase and 7-ethoxycoumarin O-deethylase activities in both groups of ellagic acid-treated animals were 33-52% and 28-43% lower than their respective non-ellagic acid-treated controls. Hepatic as well as pulmonary aminopyrine N-demethylase and epoxide hydrolase activities were unchanged in both groups of ellagic acid-treated mice. Hepatic glutathione S-transferase activity towards BP-4,5-oxide or 1-chloro-2,4-dinitrobenzene as substrates was found to be enhanced 51-79% and 38-58% in both groups of animals. H.p.l.c. analysis of organic solvent-soluble metabolites of BP by liver and lung microsomes indicated a substantial inhibition of diol formation (including BP-7,8-diol), as well as of phenols and quinones. In liver, these inhibitory effects were more pronounced after oral feeding than after intraperitoneal administration. Our results indicate that both acute and chronic administration of ellagic acid inhibits BP metabolism and/or enhances glutathione S-transferase activity. Thus the modulation of polycyclic aromatic hydrocarbon metabolism by ellagic acid may be related to the anticarcinogenic effects of this compound.
Carcinogenesis 1985 Oct
PMID:Effect of ellagic acid on hepatic and pulmonary xenobiotic metabolism in mice: studies on the mechanism of its anticarcinogenic action. 387 74

The activities of several enzymes which metabolize xenobiotics were measured and compared in freshly isolated rabbit Clara cells (50-70% purity) and alveolar type II cells (80-95% purity) or microsomal preparations from the isolated cell fractions. The presence of 1 mM nicotinamide in protease and cell isolation buffers increased significantly 7-ethoxycoumarin (7-EC) deethylase and epoxide hydrolase activities in the isolated Clara and type II cells. Isolated Clara cell fractions metabolized 7-EC to umbelliferone at a rate of 241 +/- 27 pmoles/mg prot/min (mean +/- S.E., N =5), while the 7-EC deethylation rate in type II cells was 111 +/- 15 pmoles/mg prot/min. Coumarin hydroxylation activity, however, was more than ten times greater in the Clara cells than in the type II cells on a per mg cellular protein basis. N-oxidation of N,N-dimethylaniline, catalyzed by a flavin monooxygenase, was about 2 times as great in microsomes of Clara cells as in microsomes of type II cells. Epoxide hydrolase activity with benzo(a)pyrene 4,5-oxide as substrate was about 10 times higher in Clara cells than in type II cells. Because of the greater cellular, structural and functional heterogeneity in lung, differential distribution of enzymes responsible for xenobiotic metabolism in this tissue may contribute to cell selective chemical toxicity and carcinogenesis.
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PMID:Cytochrome P-450 monooxygenase, epoxide hydrolase and flavin monooxygenase activities in Clara cells and alveolar type II cells isolated from rabbit. 391 26

A number of model systems have been developed to study the initiating and promoting phases of neoplastic development in rats liver. Four of these protocols use diethylnitrosamine (DEN) initiation, but employ different methods of promotion. The present studies were designed to evaluate these systems under standardized laboratory conditions to determine their relative ability to induce histochemically identifiable gamma-glutamyl transpeptidase positive (GGT+) foci. Studies were also performed to examine the effects of the four promoting regimens on liver-derived serum enzymes and hepatic drug metabolism. Under standardized laboratory conditions, including the use of a single rat strain, all four systems induced GGT+ foci following DEN initiation. Within the maximum time period evaluated (8 weeks) promotion with 2-acetylaminofluorene and partial hepatectomy resulted in the highest number of GGT+ foci/cm2. In addition, the hepatic mixed-function oxidase system was markedly affected by the promoting regimens. Cytochrome P-450 content was decreased (50% of control) by three of four systems. All four promotion regimens reduced benzphetamine-N-demethylase activity (20-50% of control). Ethoxycoumarin-O-deethylase activity (P-448 related) was not changed by the promotion regimens. Three of four regimens increased epoxide hydrolase activity (150-600% of control) and DT-diaphorase activity (150-200% of control). Combining DEN initiation and each of the four promotion protocols had little additional effect on hepatic drug metabolizing enzymes. It is concluded that the four systems evaluated are reproducible under standard conditions and that the promotion regimens employed cause striking alterations in hepatic microsomal drug metabolism that are largely independent of the presence or absence of focal GGT+ lesions.
Carcinogenesis 1982
PMID:Comparison of hepatic carcinogen initiation-promotion systems. 612 70

The effect of nafenopin and phenobarbitone upon the distribution of gamma-glutamyltranspeptidase activity and epoxide hydrolase antigenic sites in the liver and upon the development of enzyme-altered foci during hepatocarcinogenesis have been compared. Phenobarbitone induced gamma-glutamyltranspeptidase activity in perilobular hepatocytes. Nafenopin did not alter the distribution of this enzyme. Both compounds appeared to induce epoxide hydrolase; phenobarbitone increased the enzyme content of centrilobular cells, whilst nafenopin altered immunostaining mainly in portal regions. Hepatic lesions were induced by treating one day-old rats with diethylnitrosamine. Phenobarbitone and nafenopin were then administered in the diet upon weaning. Animals were killed after either 2, 4 or 8 weeks feeding and liver sections were stained for the two enzymes. Only sections from nitrosamine-treated animals contained enzyme-altered foci. In general, gamma-glutamyltranspeptidase-containing foci stained also for epoxide hydrolase; but many hydrolase-positive foci did not stain for gamma-glutamyltranspeptidase activity. Phenobarbitone treatment stimulated the formation of enzyme-altered foci. This effect was more marked in male animals. Nafenopin treatment suppressed the development of foci at all time points, such that less hepatic lesions were seen than in animals which received only diethylnitrosamine. The results cast doubt upon the generality of gamma-glutamyltranspeptidase as a marker for preneoplastic lesions within the liver.
Carcinogenesis 1984 Jan
PMID:Inhibitory effect of nafenopin upon the development of diethylnitrosamine-induced enzyme-altered foci within the rat liver. 614 87


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