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)

Absorption, metabolism and DNA binding of 2-nitrofluorene (NF) was studied in isolated, perfused and ventilated rat lungs and in lung microsomal incubations. Comparisons were made between control animals and animals treated with beta-naphthoflavone (BNF), a 2,3,7,8-tetrachlorodibenzo(rho)dioxin (TCDD) receptor ligand and inducer of cytochrome P450IA1. Clearance of NF increased significantly in the isolated, perfused and ventilated lungs after BNF dosage, from 0.55 +/- 0.06 ml/min to 2.37 +/- 0.62 ml/min (P less than 0.05, n = 5-6). As a consequence of this, the mean residence time (MRT) for NF decreased when NF was dosed directly to the perfusion buffer, from 213 +/- 23 min (n = 6) to 48 +/- 9 min (n = 6), and after intratracheal dosage from 289 +/- 101 min (n = 5) to 135 +/- 72 min (n = 5). Irreversible binding of NF metabolites to DNA increased 2-fold after treatment with BNF when NF was dosed to the lung perfusion buffer. Treatment with BNF increased the rate of lung microsomal NF metabolism significantly, from 54 +/- 5 to 106 +/- 11 pmol/min/mg protein (P less than 0.05, n = 6-12). Formation of the monohydroxylated metabolite X-OHNF was inhibited in vitro by addition of alpha-naphthoflavone (50 microM), by 89 and 98% with lung microsomal fractions from control and BNF-treated rats respectively. In contrast, proadifen (50 microM) preferentially inhibited formation of 9-OHNF, by 42 and 33% in incubations with lung microsomal fractions from control and BNF-treated animals. Anti-P450IIB1-IgG inhibited formation of 9-OHNF by 96 and 45% with lung microsomes from control and BNF-treated rats respectively. Formation of X-OHNF was unaffected by addition of anti-P-450IIB1-IgG in both cases. These results show that both constitutive and inducible microsomal rat lung enzymes metabolize NF. A constitutive enzyme, most likely cytochrome P450IIB1, catalyzes metabolic attack on NF with high preference for the 9-position. A BNF-inducible microsomal enzyme, most likely cytochrome P450IA1, catalyzes hydroxylation of NF both in the 9-position and in other positions. Increased metabolic clearance, metabolism and DNA binding of NF after BNF treatment suggest that the level and specificity of cytochrome P450 isozymes may be important determinants for toxicity and availability of NF in the rat lung.
Carcinogenesis 1990 Aug
PMID:2-Nitrofluorene metabolism in the rat lung. Pharmacokinetic and metabolic effects of beta-naphthoflavone treatment. 238 10

It is known that consumption of cruciferous vegetables protects against the chemical induction of cancer in many organs. It has been suggested that this protection is mediated through an effect on the cytochrome P450 monooxygenase system. This system is responsible for the activation of a number of chemical carcinogens to their ultimate forms. In the present study, the effect of indole-3-carbinol (I3C) and 5,6-benzoflavone (5,6BF) on the expression of cytochrome P450IA1 in rat colon and liver has been investigated. Cytochrome P450IA1 mRNA was induced in colon following a single oral administration of I3C or 5,6BF. A biphasic induction profile was obtained with maxima at 4 and 16 h post-administration. Both inducers caused an approximately 2-fold increase in P450IA1 mRNA at 4 h and a 10-fold increase at 16 h. In contrast, both cytochrome P450IA1 and IA2 mRNAs was increased over the control between 4 and 24 h. The total amount of P450IA mRNAs in liver at 4 and 16 h was increased about 2- and 4-fold respectively by I3C; 5,6BF induced the P450IA mRNAs 4- and 5-fold respectively. The expression of cytochrome P450IA1 and IA2 is induced by I3C and several flavones present in cruciferous vegetables. This suggests that one of the protective effects of cruciferous vegetables in the reduction of chemically induced cancer may be regulation of cytochrome P450s involved in the metabolism of the chemical carcinogens.
Carcinogenesis 1990 Aug
PMID:Induction of cytochrome P450IA1 in rat colon and liver by indole-3-carbinol and 5,6-benzoflavone. 238 12

The organochlorine pesticide 1,1'-(2,2,2-trichloroethylidene) bis(4-chlorobenzene) (DDT) and four structural analogues (bromopropylate, chlorobenzilate, dicofol and fenarimol) were investigated for their ability to inhibit gap junctional intercellular communication both in the Chinese hamster V79 metabolic co-operation assay and in the scrape-loading/dye-transfer assay in WB-F344 rat liver epithelial cells. The pesticides were also studied for their ability to enhance the development of gamma-glutamyltranspeptidase-positive altered hepatic foci and induce cytochrome P450 monooxygenase isoenzymes in nitrosamine-initiated male Sprague-Dawley rats. The in vitro studies showed all organohalogens except fenarimol to be potent inhibitors of cell-cell communication in both test systems used. Concomitant results were recorded in the in vivo study. Thus, all potent inhibitors of intercellular communication were found to enhance significantly foci development and fenarimol was again without any significant effect. All pesticides studied were shown to be potent inducers of the phenobarbital-inducible cytochrome P450b isoenzyme and to cause hepatomegaly. Thus, no strict correlation between cytochrome P450b induction/liver growth and tumour promotion-related effects in vivo and in vitro was apparent for these organohalogen pesticides in the present study.
Carcinogenesis 1990 Aug
PMID:Promotion of altered hepatic foci development in rat liver, cytochrome P450 enzyme induction and inhibition of cell-cell communication by DDT and some structurally related organohalogen pesticides. 238 28

Activities of enzymes involved in the metabolic formation and catabolism of epoxides were determined in liver subcellular preparations from 11 mammalian species and various strains of mice. The most conspicuous finding was that the activities of the microsomal epoxide hydrolase were clearly lower in the mouse than in the other species. This invited the working hypothesis that epoxides may be involved in mouse liver carcinogenesis. The carcinogens may be metabolised themselves to reactive epoxides or they may modify the metabolism of epoxides formed from endogenous or other foreign compounds. To examine the former point, phenobarbital, DDT (1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane), lindane and benzo(a)pyrene were investigated for mutagenicity in Salmonella typhimurium using as the carcinogen-metabolising system subcellular liver preparations from animals in which these compounds efficiently induce liver tumours and from resistant animals. Phenobarbital, DDT and lindane were not mutagenic under any conditions, including those where microsomal epoxide hydrolase was also inhibited. However, a DDT metabolite, 1,1-bis(p-chlorophenyl)-2,2-dichloroethane was mutagenic in strain TA98, when norharman was added to the metabolising system, rat liver postmitochondrial fraction. Benzo(a)pyrene, which efficiently induces liver tumours in male but not in female newborn C3HeB/FeJ X A/J mice, was similarly activated by liver preparations from male and female animals. This was true with and without pretreatment of the mice with an inducer of cytochrome P-448. Also, activities and inducibilities of monooxygenase, epoxide hydrolase and glutathione transferase (toward benzo(a)pyrene and benzo(a)pyrene 4,5-oxide, respectively) were indistinguishable between males and females. Therefore, differences in the metabolism of benzo(a)pyrene do not appear to be the reason for the sex difference in tumour susceptibility. Likewise, mouse strains with high and low frequencies of spontaneous and chemically-induced liver tumours did not appreciably differ in their hepatic microsomal epoxide hydrolase activities. The low level of this activity therefore cannot constitute the critical factor for the high tumour susceptibility of certain strains of mice. However the statement does not preclude potentiation of the susceptibility toward particular carcinogens owing to this metabolic trait of the mouse.
 ...
PMID:Species differences in enzymes controlling reactive epoxides. 243 83

In previous studies we have shown that substances associated with particulates collected from urban air and automobile exhaust bind with high affinity to the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) receptor present in rat liver cytosol. In this study we used a rat hepatoma cell line, H4IIE, to investigate the effect of such substances on an enzyme system, aryl hydrocarbon hydroxylase (AHH), which is regulated via the TCDD receptor. The results demonstrate that AHH activity in the H4IIE cell line can be induced by extracts of particulates collected from urban air and automobile exhausts in a dose-dependent manner, and that the AHH activity is inducible by five polycyclic aromatic hydrocarbons (PAHs) including 1-/3-nitrobenzo[a]pyrene and 6-chlorochrysene, all present in extracts of particulates from urban air and automobile exhausts. The induction of AHH activity is correlated to apparent TCDD receptor affinity for investigated PAHs (r = 0.85) and particulate extracts. Biochemically, treatment of the cells with 5,6-benzoflavone significantly increased the level of cytochrome P-450c but not P-450d as shown by immunoblotting and analysis of mRNA levels. The data indicate that substances present in extracts of urban air particulates can interact with the TCDD receptor in intact cells and cause an accumulation of cytochrome P-450c mRNA leading to an increased synthesis of the gene product and thus an increase in enzyme activity.
Carcinogenesis 1988 Jan
PMID:TCDD receptor ligands present in extracts of urban air particulate matter induce aryl hydrocarbon hydroxylase activity and cytochrome P-450c gene expression in rat hepatoma cells. 244 93

Previous studies have shown that the incidences of liver and lung tumors in mice exposed transplacentally to 3-methyl-cholanthrene (MC) were significantly influenced by the sensitivity of both mothers and fetuses to induction of cytochrome(s) P-450 by polycyclic aromatic hydrocarbons. In order to delineate further the biochemical and molecular processes underlying the observed biological effects, the inductive effect of MC and beta-naphthoflavone (beta NF) on cytochrome P-450 was determined at the biochemical and molecular levels. C57BL/6 females were mated with DBA/2 males and treated i.p. on day 17 of gestation with olive oil alone, 150 mg/kg of beta NF or different doses of MC. At various times after injection the mothers were sacrificed and the fetuses removed for biochemical and molecular studies. MC caused maximal induction of aryl hydrocarbon hydroxylase (AHH) activity by 8 h in both the liver and lung. beta NF caused nearly maximal induction of AHH activity by 8 h in the lung but had little effect on liver AHH activity at this time. Maximal induction with beta NF occurred by 24 h in both organs. Addition of monoclonal antibody 1-7-1, specific for the MC-inducible forms of cytochrome P-450 (P-450IA1 and A2), to the incubation mixtures resulted in a 55-70% inhibition of AHH activity in both lung and liver assays, regardless of the inducing agent used, while having no effect on AHH activity from oil-treated mice. RNA blot analysis carried out in parallel with enzyme assays demonstrated that the levels of enzyme activity correlated very well with the levels of steady-state RNAs. MC caused maximal induction of P-450IA1 RNA levels 4 h after injection in both organs and a biphasic secondary increase was observed in the lung. Maximal levels of P-450IA1 RNA were seen at 12-16 h following injection of beta NF. However, the ratio of P-450IA1 RNAs present at 16 versus 2 h in the beta NF-treated liver appeared greater than that in the lung. P-450IA2 was also induced in fetal liver and lung, but at low levels relative to P-450IA1. The results indicate that the increase in functional AHH activity was primarily due to induction of cytochrome P-450IA1. The differences in induction kinetics observed for cytochromes P-450IA1 and A2 suggest that these enzymes exhibit both tissue- and inducer-dependent specificity.
Carcinogenesis 1989 May
PMID:Differential induction of fetal mouse liver and lung cytochromes P-450 by beta-naphthoflavone and 3-methylcholanthrene. 246 28

The disposition of the carcinogenic (+)-7 beta, 8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9, 10-tetrahydrobenzo[a]pyrene [(+)-anti-BPDE] has been studied in isolated hepatocytes obtained from 3-methylcholanthrene-pretreated rats. In these cells different routes are acting in concert and contribute to diol-epoxide elimination. Conjugation of (+)-anti-BPDE with glutathione (GSH) and cytochrome P-450c-mediated metabolism of the diol-epoxide to 1- and 3-hydroxy-anti-BPDE (triol-epoxides) appears to be equally important. The reactive triol-epoxides undergo a number of secondary reactions, including covalent binding to cellular constituents, e.g. protein and GSH, and hydrolysis to pentahydroxyderivatives. The effective intracellular lifetime of (+)-anti-BPDE is approximately 1 min and comparable to that previously observed in hepatocytes obtained from uninduced animals.
Carcinogenesis 1989 Feb
PMID:The influence of cytochrome P-450 induction on the disposition of carcinogenic benzo[a]pyrene 7,8-dihydrodiol 9,10-epoxide in isolated cells. 249 11

We present data showing that the major phenobarbital inducible cytochromes P-450 (cytochrome P-450IIB1 and cytochrome P-450IIB2) were phosphorylated in intact hepatocytes. This phosphorylation was greatly increased by the cAMP derivatives N6-dibutyryl-cAMP and 8-thiomethyl-cAMP mediated by a cAMP-dependent protein kinase. Most importantly the phosphorylation status of cytochromes P-450 was shown to change in the hepatocytes after treatment with glucagon, which is known to increase the level of cAMP in hepatocytes. The observed impact of the hormone glucagon on the phosphorylation of distinct cytochrome P-450 forms in intact hepatocytes reveals the possibility that the enzyme activity of cytochromes P-450 could be rapidly and differentially regulated by their phosphorylation and therefore dependent on the hormonal status of the organism.
Carcinogenesis 1989 Jan
PMID:Phosphorylation of carcinogen metabolizing enzymes: regulation of the phosphorylation status of the major phenobarbital inducible cytochromes P-450 in hepatocytes. 253 70

Effect of ethanol (20% in drinking water) or acetone (1% in drinking water) treatment was investigated on N-diethylnitrosamine (DEN), acetyl-aminofluorene (AAF) and partial hepatectomy (PH) induced hepatic tumors in rats. Simultaneously with the morphological detection of foci and nodules in the liver of the sacrificed rats, the activities of isozymes of cytochrome P450IIE gene subfamily responsible for the oxidation of ethanol or acetone (as aniline hydroxylase) and also the activity of aminopyrine N-demethylase were determined. Nodules could be detected after DEN, AAF and PH treatment with and without combination with acetone, however nodules did not developed in ethanol treated animals even 6 months after the DEN injection. As expected acetone or ethanol selectively increased the activity of aniline hydroxylase without a general induction of P-450 enzymes. It is suggested that the induction of P-450IIE isoenzymes per se is not connected to the preventive effect of ethanol on DEN induced carcinogenesis.
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PMID:Ethanol treatment inhibits the development of diethylnitrosamine-induced tumors in rats. 261 30

We have isolated a human lymphoblastoid cell line with higher levels of native cytochrome P450IA1 activity and by DNA transfection introduced human cDNAs for a putative cytochrome P450IIA2 and epoxide hydrolase (E.C. 3.3.2.3). The resultant cell line, designated MCL-1, was substantially more sensitive to the mutagenicity of dimethylnitrosamine and benzo[a]pyrene than the AHH-1 cell line and was found to have increased metabolism of benzo[a]pyrene to dihydrodiols. The increase in native cytochrome P450IA1 activity was achieved by mutation and selection based on resistance to the phototoxicity of benzo[ghi]perylene. One resistant clone, designated L3, was used for subsequent studies. Two complete cDNAs, one encoding a putative cytochrome P450IIA2 and the other a microsomal epoxide hydrolase, were isolated from a human liver cDNA library. After introduction of the cDNAs into an expression vector and transfection into AHH-1 cells, gene expression was detected at the level of enzyme activity (epoxide hydrolase) or by increased sensitivity to dimethylnitrosamine cytotoxicity/mutagenicity (putative P450IIA2). A vector containing both cDNAs was then constructed and transfected into L3 cells to produce MCL-1 cells. The potential usefulness of drug-metabolizing gene transfection and of the MCL-1 cell line, in particular, for genetic toxicity testing is discussed.
Carcinogenesis 1989 May
PMID:Development of a human cell line by selection and drug-metabolizing gene transfection with increased capacity to activate promutagens. 270 43


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