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)

Chemically induced rat liver nodules and cancers characteristically demonstrate a limited capacity to activate xenobiotics to reactive species mainly because of decreased amounts of cytochrome P-450. These lesions also show enhancement of xenobiotic detoxication by such mechanisms as enzymic conjugation or reduction of cytotoxic species. We recently demonstrated a similar pattern of metabolic alteration in spontaneous mouse liver tumors. These findings suggested that certain phenotypic alterations attributed to chronic chemical exposure are inherent in the genetic program for carcinogenesis, and that they may arise independently of chronic exposure. To extend that study, we examined spontaneous and diethylnitrosamine-induced mouse liver tumors for nine enzyme activities commonly reported to be altered in chemically induced rat liver nodules and cancers. The activities of benzo(a)pyrene monooxygenase (EC 1.14.14.1), aminopyrene demethylase, cytochrome P-450 reductase, epoxide hydrolase (EC 3.3.2.3), and UDPglucuronosyl transferase (EC 2.4.1.17) in microsomes from spontaneous tumors relative to those from normal liver were 0.25, 0.43, 1.27, 0.90, and 0.51, respectively. Similar values were obtained with microsomes from chemically induced tumors. The activities of DT-diaphorase (EC 1.6.99.2), glutathione reductase (EC 1.6.4.2), glutathione S-transferase (EC 2.5.1.18), and glutathione peroxidase (EC 1.11.1.9) in cytosol from spontaneous tumors relative to cytosol from normal liver were 2.24, 2.0, 2.43, and 0.31, respectively. Similar values were obtained with cytosol from chemically induced tumors. These results demonstrated that a significant portion of the enzymic phenotype observed in chemically induced rat liver nodules and cancers, which may confer resistance to cytotoxic chemicals, is manifest in spontaneous and chemically induced mouse liver tumors. Further, initiated cells that exhibit this phenotype replicated and progressed in the absence of continued chemical selection.
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PMID:Xenobiotic metabolizing enzymes in genetically and chemically initiated mouse liver tumors. 308 73

Competition between a hydroxylated metabolite and the parent polycyclic aromatic hydrocarbon (PAH) for metabolism at cytochromes P-450 may result in the generation of hydroxylated dihydrodiol epoxides. The effectiveness of the competition between 7-hydroxymethyl-12-methylbenz[a]anthracene (7HOMMBA) or 12-hydroxymethyl-7-methylbenz[a]anthracene (12HOMMBA) and 7,12-dimethylbenz[a]anthracene (DMBA) is highly dependent on the form(s) of cytochrome P-450 in the microsomes. The inhibitory effects of exogenously added 7HOMMBA or 12HOMMBA on DMBA metabolism were 30- to 50-fold greater in 3-methylcholanthrene (MC)-induced rat liver microsomes (Ki = 0.4 microM) compared to either uninduced or phenobarbital (PB)-induced liver microsomes (Ki = 14 and 11 microM, respectively). Similarly, product inhibition of total DMBA metabolism by metabolites generated in situ was significant only in MC-induced liver microsomes (Ki' = 2.5 microM). Metabolism of 7HOMMBA in these microsomes was strongly restricted by an unusual substrate inhibition derived from the inhibitory binding of a second molecule of 7HOMMBA. This same phenomenon was observed with reconstituted cytochrome P-450c but not with PB-induced or uninduced microsomes. Complex formation by binding of DMBA, 7HOMMBA, and 12HOMMBA to purified P-450c reconstituted in phospholipid micelles was determined by optical spectroscopy and fluorescence quenching. Binding affinities of both the 7HOMMBA and 12HOMMBA (Kd = 95 and 110 nM, respectively), were 2.5-fold higher compared to that of DMBA (Kd = 265 nM). These results provide a first demonstration that hydroxylation of a PAH can lead to preferential metabolism through an increased affinity for cytochrome P-450.
Carcinogenesis 1986 Jun
PMID:Selective interactions of cytochromes P-450 with the hydroxymethyl derivatives of 7,12-dimethylbenz[a]anthracene. 308 67

A form of cytochrome P-450 is produced in Saccharomyces cerevisiae strain D7 during the logarithmic growth phase in 20% glucose liquid medium. This form was inhibited by metyrapone, tetrahydrofuran and by carbon monoxide, specific inhibitors of cytochrome P-450 in mammals. The inhibition was observed by means of the increase of the genetic activity of 4-nitroquinoline 1-oxide (4-NQO) on logarithmic growth phase cells of D7 strain, adding the inhibitors to the incubation mixture. 4-NQO is a strong direct mutagen on stationary phase cells that is detoxified by the monooxygenase system. The inhibition was measured by determining the decrease of the O-deethylation of 7-ethoxycoumarin in whole cells of yeast depending on different concentrations of inhibitors. A decrease of O-deethylation activity was found in the presence of tetrahydrofuran and metyrapone and this behaviour is typical of the cytochrome P-450 species induced by ethanol, as in mammals. Adding sodium phenobarbital to 0.5% glucose liquid medium, a form inhibited only by metyrapone was obtained. The presence of different inducible forms of cytochrome P-450 is evident.
Carcinogenesis 1986 Jul
PMID:Specific inhibitors of the monooxygenase system of Saccharomyces cerevisiae modified the mutagenic effect of 4-nitroquinoline 1-oxide and the deethylation activity of the yeast. 308 45

It is generally held that altered areas, neoplastic nodules and hepatocellular carcinomas (HCC) induced by mutagenic chemical carcinogens are resistant to the effects of hepatotoxins. This characteristic is attributed to the marked decrease in activating (phase I) enzymes and a several-fold increase in detoxifying (phase II) enzymes. In previous studies, we have shown that hepatic neoplastic lesions induced by non-mutagenic peroxisome proliferators differed from mutagenic carcinogen-induced lesions by lacking gamma-glutamyl transpeptidase and the placental form of glutathione S-transferase. In this study we have examined ciprofibrate-induced HCC for phase I and phase II enzymes. These tumors showed a marked decrease in cytochrome P-450 (53%), cytochrome b5 (79%) and aryl hydrocarbon hydroxylase (55%) activities compared to normal livers. Interestingly, activities of phase II enzymes in these tumors, such as UDP-glucuronyltransferases and sulfotransferases were decreased or remained the same as in the normal livers. In addition, the activity of epoxide hydrolase was also decreased markedly in all peroxisome proliferator-induced HCC. The decrease in the activity of various enzymes appears not to be due to the direct effect of ciprofibrate, since no inhibitory effect was observed after adding this compound in vitro. These findings further amplify the differences between the hepatic lesions induced by mutagenic hepatocarcinogens and non-mutagenic peroxisome proliferators suggesting a divergence in the mechanism by which peroxisome proliferators induce liver tumors.
Carcinogenesis 1987 Jan
PMID:Peroxisome proliferator-induced hepatocarcinogenesis: levels of activating and detoxifying enzymes in hepatocellular carcinomas induced by ciprofibrate. 310 85

Rat mammary epithelial cells (RMEC) in culture have been shown to activate polycyclic aromatic hydrocarbon (PAH) carcinogens. This study investigates the role of mammary cytochrome P-450 monooxygenases in these metabolic processes. Monooxygenation of 7,12-dimethylbenz[a]anthracene (DMBA) by RMEC in culture exhibited a 6-h lag period before reaching a constant rate. The mechanism for this time-dependent expression of DMBA monooxygenase activity was investigated in lysed cells, where both conjugation and in situ induction of P-450 are prevented. Although metabolism of DMBA by untreated RMEC lysates was undetectable (less than 1 pmol/mg cell protein/h), prior exposure of cultured cells to benz[a]anthracene (BA) induced DMBA metabolism, (approximately 100 pmol/mg cell protein/h). BA pretreatment also eliminated the lag period for metabolism of DMBA by cultured RMEC but did not prevent additional induction of DMBA monoxygenase activity by the substrate. The distribution of monooxygenated DMBA metabolites formed by BA-induced cell lysates was clearly different from that obtained with purified P-450c, the predominant PAH-inducible isozyme in rat liver. For example, the carcinogen precursor DMBA 3,4-dihydrodiol, which is not formed by P-450c, was a clearly detectable product in RMEC. The low epoxide hydratase activity of BA-induced lysate (approximately 400-fold lower compared to that in the liver) limited formation of all DMBA dihydrodiols. The formation of DMBA 3,4-dihydrodiol increased by 5-fold following addition of exogenous purified epoxide hydratase. The DMBA monooxygenase activity of BA-induced RMEC lysates was completely inhibited by alpha-naphthoflavone but was only partially inhibited (50%) by a polyclonal antibody raised against cytochrome P-450c. Anti P-450c completely inhibited formation of some of the metabolites, partially inhibited formation of others and notably stimulated formation of DMBA 3,4-dihydrodiol by 60%. A polyclonal antibody that recognized both rat hepatic P-450a and a group of P-450 isozymes related to P-450h, and which totally inhibited DMBA 3,4-dihydrodiol formation by rat liver microsomes, did not inhibit formation of any DMBA metabolite in RMEC, including DMBA 3,4-dihydrodiol. Western blot analyses of RMEC homogenates demonstrated that BA pretreatment induces P-450c, but not P-450a or any of the P-450h-related isozymes. We conclude that metabolism of DMBA by RMEC depends on induction of P-450c and at least one additional form of cytochrome P-450 which is immunochemically distinct from rat hepatic P-450a and P-450h related isozymes, but is sensitive to alpha-naphthoflavone.
Carcinogenesis 1987 Jan
PMID:Induction of mammary cytochromes P-450: an essential first step in the metabolism of 7,12-dimethylbenz[a]anthracene by rat mammary epithelial cells. 310 87

Monocrotaline (MCT), a hepatotoxic/hepatocarcinogenic pyrrolizidine alkaloid (PA) induced DNA-DNA interstrand crosslinks in a dose-dependent manner through 30 mg/kg. Hepatic cytochrome P-450 has been shown to bioactivate MCT to pyrrole derivatives which are thought to be responsible for these genotoxic lesions. We have hypothesized these lesions to be related to the adverse hepatic actions of MCT and other PAs. Studies reported here investigated the effect of phenobarbital, a P-450 inducer, 2-dimethylaminoethyl-2,2-diphenylvalerate, a P-450 inhibitor and butylated hydroxyanisole, a dietary antioxidant, on hepatic DNA-DNA interstrand cross-links induced by a single dose of MCT (15 mg/kg i.p.) administered to male Sprague-Dawley rats. DNA damage was assessed by alkaline elution. The effects of these pretreatment regimens on MCT-induced DNA-DNA interstrand cross-linking was qualitatively similar to their reported effects on the hepatotoxicity of MCT. The effects of these pretreatments on hepatic cytochrome P-450 content, hepatic non-protein sulfhydryl levels and hepatic glutathione S-transferase activities were similarly investigated in attempts to explain the observed effects on DNA cross-link induction. These data provide further support for the association between DNA damage and the adverse hepatic effects of MCT.
Carcinogenesis 1987 Mar
PMID:Modulation of monocrotaline-induced hepatic genotoxicity in rats. 310 99

Renal carcinoma in male Syrian hamsters, induced by chronic administration of estradiol for 5-7 months, is known to arise in the cortex at the cortico-medullary junction. In this in vivo model for hormonal carcinogenesis, estrogen-induced covalent DNA adducts have previously been observed in whole kidney and have been postulated to be involved in tumor induction. In the present study, the intrarenal distribution of estrogen-induced DNA modification and estrogen metabolizing enzymes were investigated in male Syrian hamsters to ascertain a role of metabolism and adduct formation in estrogen-induced carcinogenesis. The highest estrogen-induced DNA adduct concentrations as measured by 32P-postlabeling analysis were found in the renal cortex of hamsters treated with estradiol for 7 months. Total adduct levels in medullary DNA were approximately one-half of those found in cortex. Cytochrome P-450 enzymes were detected only in microsomes of kidney cortex (approximately 0.8 +/- 0.6 nmol P-450/mg protein) but not medulla of untreated male Syrian hamsters. Prostaglandin endoperoxide synthase activity in kidney cortical microsomes was 1/5 of the activity found in medullary microsomes. Thus, microsomal cytochrome P-450 levels and estrogen-induced DNA adduct formation were highest in hamster kidney cortex, the origin of renal tumorigenesis. It is postulated that estrogen metabolism by cytochrome P-450 enzymes leading to covalent DNA modification plays a role in hormonal carcinogenesis in the hamster kidney.
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PMID:Localization of estrogen-induced DNA adducts and cytochrome P-450 activity at the site of renal carcinogenesis in the hamster kidney. 310 11

Previous studies have shown that dietary R-goitrin is a potent inducer of hepatic glutathione S-transferase (GST) and epoxide hydrolase activities but has no effect on components of the mixed function oxidase system (ethoxycoumarin O-deethylase and cytochrome P-450). In the present work effects of dietary R-goitrin (200 p.p.m.) or butylated hydroxyanisole (BHA) (7500 p.p.m.) on GST activity, binding of aflatoxin B1 (AFB1) to DNA, in vivo, and biliary excretion of thiol conjugates of AFB1 in rats were studied. Increases of GST activities (1.9- and 2.1-fold) were accompanied by reductions in AFB1-DNA binding (43% and 85%) and increases (1.7- and 2.2-fold) in biliary excretion of AFB1-thiol conjugates in R-goitrin and BHA groups, respectively. Microsomal aflatoxin 8,9-epoxidase activities were not increased in either treatment group. The role of GST induction in the carcinogenesis of AFB1 and the anticarcinogenic potential of R-goitrin are discussed.
Carcinogenesis 1987 Apr
PMID:R-goitrin- and BHA-induced modulation of aflatoxin B1 binding to DNA and biliary excretion of thiol conjugates in rats. 310 48

Metabolic activation and/or deactivation of indole alkaloid tumor promoter, (-)-indolactam V (ILV), was examined using rat liver microsomes. Reaction of ILV with the microsomes supplemented with NADPH and MgCl2 gave three major metabolites, which were identified as (-)-N13-desmethylindolactam V and two diastereomers of (-)-2-oxyindolactam V at C-3. The tumor-promoting activities of these metabolites were evaluated by induction of Epstein-Barr virus early antigen and inhibition of specific binding of [3H]-12-O-tetradecanoylphorbol-13-acetate to a mouse epidermal particulate fraction, and proved to be conspicuously lower than that of ILV. These results demonstrate that the metabolism of ILV results in detoxification, and that it itself is the tumor-promoting entity. Studies on the enzymes concerned with this metabolism suggested the involvement of cytochrome P-450-containing mixed-function oxidases. Similar deactivation seems to be possible by skin, where the mixed-function oxidases are known to exist.
Carcinogenesis 1987 Jul
PMID:The metabolism of indole alkaloid tumor promoter, (-)-indolactam V, which has the fundamental structure of teleocidins, by rat liver microsomes. 310 58

The purpose of this work was to study the relative activities and stabilities of phase-I and phase-II drug metabolizing enzymes in incubation mixtures used in vitro genotoxicity testing in order to optimize the conditions of the assay, increase sensitivity and eliminate false negative results. Cytochrome P-450, NADPH-cytochrome P-450 (cytochrome c) reductase activity and various phase-I and phase-II enzyme activities of the drug-metabolizing system were determined in incubation mixtures used in liver microsomal assays. The behaviour of aminopyrine N-demethylase and p-nitroanisole O-demethylase activities as phase-I markers have been reported previously. Other activities measured were glutathione S-transferase, glutathione S-epoxide transferase and epoxide hydrase, and lipid peroxidation (LP) was determined. The experiments were carried out on liver S9 fractions derived from non-induced mice or mice induced with sodium phenobarbital (PB), and/or beta-naphthoflavone (beta-NF). The phase-II enzymes were much more stable (70-90% residual activity) than phase-I enzyme activities (35-60%) in all conditions tested. The residual cytochrome P-450 was approximately 70% stable and the remaining activity of NADPH-cytochrome c-reductase about 80%, indicating that this latter enzyme does not limit the rate of the monoxygenase system in these conditions. Phase-II enzymes were induced to a smaller extent (about 2 times) than in phase-I enzymes (5-6 times) by beta-NF + PB. NADPH-cytochrome c-reductase behaved as phase-II enzymes in this respect as well as for stability. LP was appreciably higher in non-induced than in induced animals. Treatment with the beta-NF + PB mixture, however, showed that induced enzymes were more stable than those obtained by simple induction with either beta-NF or PB alone. These results lead to the conclusion that prolonged incubation times in mutagenicity assays are unnecessary when considering the relative stabilities of the various phase-I and phase-II enzyme activities in the drug-metabolizing system.
Carcinogenesis 1987 Sep
PMID:Stability of drug metabolizing enzymes during the incubation conditions of the liver microsomal assay with non-induced and induced mouse liver S-9 fractions. 311 50


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