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

1. The spatial parameters and electronic structures of 100 exogenous and endogenous chemicals have been determined by computer graphics, from which their oxidative metabolism by the cytochrome P-448 (activation) or the other families of cytochromes P-450 (generally detoxication) have been predicted. 2. The spatial parameters of these chemicals primarily determine the family of cytochrome P-450 by which the chemicals are metabolized and the electronic structures primarily determine their ease of oxidative metabolism. 3. The role of oxidative metabolism of xenobiotics by the cytochromes P-448, and their binding to the cytosolic Ah receptor, are considered in relationship to the mechanisms of chemical toxicity, mutagenicity, carcinogenicity, and co-carcinogenicity. 4. The mechanisms of chemical toxicity and carcinogenesis are considered in respect of activation through cytochrome P-448-mediated, conformationally-hindered oxygenation to reactive intermediates which, unlike most cytochrome P-450-oxygenated metabolites, are not acceptable substrates for conjugation and detoxication and therefore react with essential intracellular macromolecules. 5. The computer graphic method of determining the molecular conformations and electronic structures of molecules is a rapid, scientifically-based procedure for evaluation of the potential toxicity, mutagenicity and carcinogenicity of chemicals.
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PMID:Metabolic activation of carcinogens and toxic chemicals. 319 23

Dependence of polycyclic aromatic hydrocarbon (PAH)-induced mutagenicity on the bay region of the molecule and on the activating cytochrome P-450 enzyme was studied. Eleven PAHs with and six without a bay region were activated by postmitochondrial supernatants from control and 3-methylcholanthrene (MC)-pretreated C57BL/6 mice and from control, MC- and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-pretreated DBA/2 mice and from control and MC-pretreated Sprague-Dawley and Lewis rats. S-9 fractions from MC- or TCDD-treated animals induced more mutagenicity with PAHs with a bay region compared with S-9 fractions from control animals or MC-treated D2 mice. Mutagenicities of PAHs without a bay region were largely independent of the source of activating enzyme. There were three exceptions, namely benzo[e]pyrene, phenanthrene and perylene (each possessing a bay region), which were not mutagenic. These studies support the notion that the Ah-locus-controlled induction of cytochrome P1-450 activating PAHs into reactive intermediates at the bay region of the hydrocarbon molecule is of prime importance in the mutagenicity of PAHs. Qualitative correspondence to carcinogenicity is also apparent.
Carcinogenesis 1987 Jun
PMID:Mutagenicity studies of different polycyclic aromatic hydrocarbons: the significance of enzymatic factors and molecular structure. 330 Oct 44

The effect of the monoclonal antibody MAb 2-66-3, directed against the major rat liver phenobarbital (PB)-induced cytochrome P-450 (P-450), on the S9-mediated mutagenicity of N-nitrosodimethylamine (DMN) in Salmonella typhimurium strain TA1530 was studied using liver S9 from PB-treated mice. This MAb enhanced approximately 2-fold S9-mediated mutagenicity of DMN but inhibited both its N-demethylation and N-denitrosation by 50%. Thus MAb-mediated enhancement of DMN mutagenesis does not result from altered activation/inactivation pathways, both known to involve P-450 isozymes. DMSO, a hydroxyl radical (HO.) scavenger and desferrioxamine, an inhibitor of HO.-dependent reactions, quenched the MAb-mediated enhancement of DMN mutagenesis, implicating the HO.-dependent activation of DMN to mutagenic species. As a mechanism, we propose that the binding of this MAb to P-450 isozyme implicated in DMN metabolism decreases the functional coupling between the reductase and the P-450 complex, leading to an increased electron flow from the reductase towards molecular oxygen to form reduced oxygen species (HO.) at the expense of the monooxygenase functions.
Carcinogenesis 1987 Dec
PMID:A monoclonal antibody against cytochrome P-450 enhances mutagen activation of N-nitrosodimethylamine by mouse liver S9: studies on the mode of action. 331 87

Male F344/NCr rats, 6 wk old, were fed 500 ppm of phenobarbital (PB) or equimolar doses of either 5-ethyl-5-phenylhydantoin (EPH) or 5,5-diethylhydantoin (EEH) in diet for 2 wk and hepatic cytochrome P-450-mediated alkoxyresorufin O-dealkylase and aminopyrine N-demethylase activities were determined. Both PB and EPH greatly increased P-450-mediated enzyme activities in rat liver while EEH was ineffective. To evaluate the hydantoins as tumor promoters, 5-wk-old male F344 rats were given a single i.p. injection of 75 mg N-nitrosodiethylamine/kg body weight. Beginning 2 wk later, they were placed either on normal diet or diet containing 500 ppm of PB or equimolar doses of EPH or EEH for the remaining experimental period. Control groups received an i.p. injection of saline followed by each of the test diets. Animals were sacrificed at either 52 or 78 wk. PB and EPH significantly enhanced the development of hepatocellular foci and hepatocellular adenomas at 52 wk and hepatocellular carcinomas at 78 wk in N-nitrosodiethylamine-initiated rats. Neither the incidence of hepatocellular neoplasms nor the number and size of hepatocellular foci was significantly increased by EEH. At 78 wk, both PB and EPH enhanced the development of thyroid follicular cell neoplasms in N-nitrosodiethylamine-initiated rats while no such enhancement was observed with EEH. Thus, EPH, a long-acting sedative/anticonvulsant, like the structurally similar PB, promoted hepatocellular and thyroid follicular cell carcinogenesis and induced the PB-inducible form(s) of cytochrome P-450 (P-450b) in rats. In contrast, EEH unlike barbital failed to promote hepatocellular and thyroid follicular cell carcinogenesis and also failed to induce PB-inducible form(s) of cytochrome P-450 in rats.
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PMID:P-450 enzyme induction by 5-ethyl-5-phenylhydantoin and 5,5-diethylhydantoin, analogues of barbiturate tumor promoters phenobarbital and barbital, and promotion of liver and thyroid carcinogenesis initiated by N-nitrosodiethylamine in rats. 335 11

DBA/2, BALB/c or (BALB/c X DBA/2)F1 (CDF1) mice of both sexes were treated for 1 week with a dietary hepatocarcinogenic tryptophan pyrolysate component (Trp P-1 or Trp P-2), and the activity of hepatic microsomal enzyme(s) for mutagenic activations of Trp P-1 and Trp P-2 were assessed by means of a mutation test with Salmonella typhimurium TA98. In both Ah-responsive (BALB/c and CDF1) and Ah-nonresponsive (DBA/2) mice, the dietary treatment with Trp P-1 or Trp P-2 resulted in a significant increase of the enzyme activity for mutagenic activations of Trp P-1 and Trp P-2 in females but not in males, except the case of male BALB/c mice treated with dietary Trp P-1. Also induction of enzyme(s) in female mice was suppressed by an administration of testosterone. The induced hepatic microsomal enzyme(s) was demonstrated to be cytochrome P-450 isozyme(s) (mol. wt of 55,000 daltons) by immunoblots with use of an anti-rat cytochrome P-448 monoclonal antibody and by selective inhibition of the activity by addition of 7,8-benzoflavone into the mutation assay system. These findings indicate that carcinogenic aromatic amines such as Trp P-1 and Trp P-2 are able to induce hepatic cytochrome P-450 isozyme(s) not only in Ah-responsive mice (BALB/c and CDF1) but also in Ah-nonresponsive DBA/2 mice and that the cytochrome P-450 induction is controlled by androgen(s).
Carcinogenesis 1988 Apr
PMID:Hepatic cytochrome P-450 isozyme(s) induced by dietary carcinogenic aromatic amines preferentially in female mice of DBA/2 and other strains. 335 64

Most drugs and xenobiotics are lipid-soluble compounds that need to be transformed into more polar water-soluble molecules by a system of hepatic monoxygenases in order to be excreted by the kidney and the liver. This system is also called cytochrome P-450. It is found in animals, as well as plants. It is located in the cellular endoplasmic reticulum of numerous tissues, but it is most active in the liver. It is made up of several isoenzymes differing from one another by the structure of their apoproteins, their immunological characteristics and their affinity for various substrates. Cytochrome P-450 has great variability, being influenced by exogenous factors (drug intake, ionizing radiation, stress, diet) and individual endogenous factors (age, sex, genetic factors). Several non specific tests exploring the system are available. They include: direct investigations carried out on liver biopsies, which are seldom used in clinical practice, and indirect investigations, such as the measurement of the clearance of exogenous substances, of urinary metabolites of endogenous substances and of specific enzymes. Induction and inhibition of microsomal activity are of the utmost interest to the clinician in various fields such as toxicology, carcinogenesis, drug interactions or drug habituation, metabolic regulations and maintenance of body homeostasis. Seven classes of enzyme inducers have been defined, but the exact mechanism of this has only been identified for two of them (the barbiturate and polycyclic hydrocarbon groups). Several drugs have been identified as enzyme inhibitors, the best known to the anaesthesiologist being macrolide antibiotics, imidazole derivatives, cimetidine, chloramphenicol and isonazide.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Hepatic mono-oxygenases]. 336 13

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

Analysis of male Sprague--Dawley rat hepatic cytosol from two commercial animal laboratories for the polycyclic aromatic hydrocarbon (PAH) 4-5S binding protein showed that in one group of animals no 4-5S protein was detectable (-4S) whereas the levels of this protein were 208 +/- 57 fmol/mg cytosolic protein in the +4S rats. The role of the 4-5S binding protein in the transregulation of the cytochrome P-450-dependent monooxygenase, aryl hydrocarbon hydroxylase (AHH), was therefore investigated in the -4S and +4S Sprague-Dawley rats. The dose-response curves for the induction of hepatic microsomal AHH by 3-methylcholanthrene (MC) were indistinguishable in both +4S and -4S rats and comparable results were observed for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as an inducer. Both MC and TCDD exhibit high binding affinities for the aryl hydrocarbon (Ah) 8-9S receptor protein, whereas MC but not TCDD bound with high affinity to the 4-5S binding protein. Benzo[a]pyrene (B[a]P) binds with moderate affinity to both the Ah receptor and 4-5S binding protein and induces AHH in both -4S and +4S rats. Perylene binds with moderate affinity to the 4-5S binding protein but does not interact with the Ah receptor. This PAH was inactive as an inducer of AHH in +4S and -4S Sprague-Dawley rats. These results show that there was a correlation between the Ah receptor binding affinities of MC, B[a]P and perylene and their potencies as AHH inducers in Sprague-Dawley rats, and this corresponds to previous correlations for the induction of AHH in rat hepatoma H-4-II E cells in culture. In contrast no such correlations existed between the AHH induction potencies of these polynuclear aromatic hydrocarbons and their affinities for the 4-5S binding protein. These data, coupled with the fact that the absence of the 4-5S binding protein in the -4S Sprague-Dawley rats did not affect AHH inducibility by MC, B[a]P or perylene, suggests that the 4-5S binding protein does not play a role in the transregulation of cytochrome P-4501A1 in the rat or rat hepatoma cells in culture.
Carcinogenesis 1988 Aug
PMID:Role of the 4-5S binding protein in the induction of aryl hydrocarbon hydroxylase in the rat. 340 44

The changes in the hepatic drug metabolizing enzymes induced by the liver tumor promoter thiobenzamide (TB) were investigated. Feeding of TB to rats at a promoting regimen (1 g/kg of diet for 2 weeks) resulted in a significant decrease in the amount of liver microsomal cytochrome P-450 and of total heme. Also, the activity of cytochrome P-450 dependent monooxygenases (aminopyrine demethylase, arylhydrocarbonmonooxygenase and ethoxycoumarindeethylase) and FAD-containing monoxygenase (N,N-dimethylaniline N-oxidase and TB S-oxidase) were depressed. By contrast, phase II enzymes such as epoxide hydrase, UDP-glucuronyl transferase and GSH-transferase were significantly induced. This overall change in the drug metabolizing system was associated with tolerance of the liver towards a high necrogenic dose of TB itself as well as with an increase of mitoses and apoptosis of the hepatocytes. The findings suggest a possible relationship between this TB-induced adaptive response and the promoting activity of the compound on liver carcinogenesis.
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PMID:Changes in the rat liver drug metabolizing system during a short thiobenzamide feeding cycle. 343 87


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