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)

Oxidative metabolism (OM) of paracetamol was studied in 19 patients with hepatocellular carcinoma (HCC), 39 with chronic hepatitis B virus infection (CHBV) and 26 healthy controls. Paracetamol (1.5 g) was given and the subsequent 24 h urine collection assayed for paracetamol and its metabolites by HPLC. HCC patients showed greatly increased OM, as reflected by the combined fractional recoveries of mercapturic acid and cysteine conjugates (22%), in comparison with controls (7%) and CHBV patients (10%). As the cytochrome P-450 dependent OM of xenobiotics has been implicated in carcinogenesis, it is interesting that two CHBV patients also had increased OM.
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PMID:Increased oxidative metabolism of paracetamol in patients with hepatocellular carcinoma. 185 Oct 52

Cruciferous plant foods contain large quantities of secondary plant metabolites that have been shown to inhibit chemically induced carcinogenesis in animals. One mechanism by which these chemicals may inhibit carcinogenesis is through the induction of enzymes, such as cytochrome P-450-dependent monooxygenases, glutathione S-transferases (GST) or epoxide hydrolases (EH), which metabolize carcinogens to more polar and excretable forms. Cruciferous vegetables of the Brassica genus (e.g. Brussels sprouts, cauliflower, broccoli) contain micrograms/g levels of an indolylmethyl glucosinolate commonly known as glucobrassicin. Upon disruption of the plant material, as in food preparation or chewing, a thioglucosidase-mediated autolytic process ensues generating indole-3-carbinol (I3C), glucose, and thiocyanate ion. At acid pH comparable to that found in the stomach, I3C forms to wide variety of condensation products ranging from linear and cyclic dimers, trimers and tetramers to extended heterocyclic compounds such as indolocarbazoles. Experiments reviewed here indicate that these indole-condensation products are the compounds responsible for some of the alterations in carcinogen metabolism observed in animals fed either I3C or any of several Brassica plant foods.
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PMID:Modification of carcinogen metabolism by indolylic autolysis products of Brassica oleraceae. 189 90

Biotransformation or drug-metabolising enzymes have an important function in the detoxication of ingested toxic, carcinogenic, or tumour promoting compounds. Enzyme activity and isoenzyme composition of three biotransformation systems: glutathione S-transferase, uridine diphosphate-glucuronosyltransferase, and cytochrome P-450 were studied in normal small and large intestinal mucosa from three kidney donors. The activity of most drug-metabolising enzymes decreases slightly from proximal to distal small intestine, whereas in the mucosa of the large intestine a sharp fall in activity was observed. The isoenzyme composition for each of the three biotransformation systems changed from the small to the large intestine. Class Alpha glutathione S-transferases were not expressed in the colon, in contrast to the small intestine where both Alpha and Pi class isoenzymes are present. In addition, with monoclonal antibodies fewer protein bands for UDP-glucuronosyltransferases and cytochrome P-450 were detected in the colon. In the small intestine both isoforms P-450(4) and P-450(5) were present, whereas in the colon only reduced amounts of cytochrome P-450(4) could be visualised. For UDP-glucuronosyltransferase, 53 and 54 kDa proteins could be detected in the small intestine, but in the colon there was only weak staining of the 54 kDa band. In the normal human colon enzymes are less active and there are fewer isoenzymes present in the mucosa than in the small intestine. This implies a lower level of the detoxifying potential in the colon, which might be important in regard to the high rates of carcinogenesis in the colon.
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PMID:Biotransformation enzymes in human intestine: critical low levels in the colon? 190 9

Activity-directed fractionation of Trifolium pratense resulted in isolation of the isoflavone biochanin A, a potent inhibitor of metabolic activation of the carcinogen benzo[a]pyrene (B[a]P) in cells in culture. To determine the structural features required for maximal inhibition of cytochrome P-450 mediated metabolism of B[a]P, the inhibitory potencies of 23 flavonoids on metabolism of B[a]P to water-soluble derivatives were examined in liver S-9 homogenate from rats induced with Aroclor 1254. Flavones were much more efficient inhibitors than their corresponding isoflavone or flavanone analogs. Most flavonols were as effective inhibitors as their flavone analogs with the exception of kaempferide. Flavones with two hydroxyl or two methoxyl groups at positions 5 and 7 were the most active. Although all eight flavonoids tested effectively inhibited B[a]P metabolism by beta-naphthoflavone-induced microsomes, none were very effective inhibitors of B[a]P metabolism by phenobarbitol-induced microsomes, and only three were effective inhibitors of B[a]P metabolism by microsomes from non-induced rats. These results indicate that flavones or flavonols that contain free 5- and 7-hydroxyls are potent inhibitors of P-450 induced by beta-naphthoflavone (P-450IA1 and/or P-450IA2) and may potentially be useful as chemopreventive agents against hydrocarbon-induced carcinogenesis.
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PMID:Effects of synthetic and naturally occurring flavonoids on benzo[a]pyrene metabolism by hepatic microsomes prepared from rats treated with cytochrome P-450 inducers. 191 23

PCBs are compounds whose physical/chemical properties led to their wide spread commercial use. The persistence and stability of PCBs have resulted in a world wide distribution. PCDFs, ones of PCB derivatives, are primary causal agents of mass food poisoning, called Yusho in Japan and Yu-Cheng in Taiwan. Several epidemiologic studies on the carcinogenicity of PCBs in both occupational exposure and accidental intoxication suggest that PCBs might be a potent carcinogen in liver and lung. Many investigators reported that PCBs induced hepatocellular carcinoma in rat and mice. Although either mutagenic or genotoxic effects of PCBs are not definite, their tumor promoting effects have been repeatedly demonstrated in the liver. The effects of PCBs as tumor promoter in the lung have also been reported. PCB congeners that efficaciously promote carcinogenesis increase cytochrome P-450-dependent monooxygenases, which are abundant both in bronchiolar Clara cells and in hepatocytes. PCB congeners which are inducers of P-450 may be active as tumor promoter by inhibiting intercellular communication and/or by stimulating cell proliferation. Furan derivatives like PCDFs have high affinity to bronchiolar Clara cells and hepatocytes. PCDFs induce necrosis and epoxide formation to their target cells, which might result in carcinogenesis of liver and lung.
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PMID:[Carcinogenic effects of polychlorinated biphenyls (PCBs) and their derivatives, including carcinogenicity to the lung]. 191 96

The soybean-derived Bowman-Birk inhibitor (BBI) has been shown to inhibit carcinogenesis in both in vitro and in vivo model systems. In the present study, protease enzyme activity in selected tissues of male strain A mice was measured by hydrolysis of the synthetic substrate Boc-Val-Pro-Arg-MCA (t-butoxycarbornylvalylprolylarginine 7-amido-4-methylcoumarin). When added to homogenates of lung, liver and kidney in vitro, purified BBI inhibited hydrolytic activity at concentrations ranging from 10-100 microM. In vivo, hydrolytic activity was found to be significantly and in a dose-dependent manner, decreased in the lung as early as 2 h after i.p. injection of purified BBI. Less inhibition was found in the liver and kidney after in vivo administration of purified BBI. A crude preparation of BBI, given at 100 mg/kg, had no influence on the overall disposition of radiolabeled benzo[alpha]pyrene in mice although it decreased the hepatic activities of cytochrome P-450, 7-ethoxycoumarin-O-deethylase and ethoxy resorufin-O-deethylase. It is concluded that the chemopreventive effects of BBI on mouse lung tumor development are most likely mediated through its protease-inhibitory properties in the target organ rather than by a non-specific effect on metabolism and disposition of carcinogens.
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PMID:Acute effects of the Bowman-Birk protease inhibitor in mice. 194 45

Four novel nontransformed epithelial cell lines, isolated from fetal or adult mouse liver, were tested: (a) to determine the profile of xenobiotic metabolizing enzymes; (b) to evaluate the inducibility of the polysubstrate (cytochrome P-450-dependent) monooxygenase system by various classes of inducers; and (c) to assess the capacity of the cells to metabolize structurally different procarcinogens. With regard to the phase I pathway, the cells expressed various P-450 (class IA, IA2, IIB, IIE1, IIIA) and flavin adenine dinucleotide-containing monooxygenase-dependent bio-transformation enzyme activities at levels (in lines C2.8 and C6) comparable with those present in murine adult liver preparations. The expression of various P-450s was demonstrated also by immunoprecipitation assays using rabbit polyclonal antibodies. For the phase II pathway, cells expressed substantial levels of glutathione S-transferase, glutathione S-epoxide transferase, and UDP-glucuronosyltransferase. Low expression of epoxide hydrolase was observed. Induction of P-450 function by sodium phenobarbital, beta-naphthoflavone, isosafrole, ethanol, and pregnenolone 16 alpha-carbonitrile, monitored using specific P-450-linked activities, was considerably elevated (over 5-fold in class IIB with the C2.8 and C6 cell lines). The most competent C2.8 and C6 cell lines were able to activate benzo(a)pyrene, cyclophosphamide, dimethylnitrosamine, diethylstilbestrol, and 2-naphthylamine as shown by the significantly increased frequencies of mitotic gene conversion, mitotic crossing-over, and point [reverse] mutation in the diploid D7 strain of Saccharomyces cerevisiae after 4 [cyclophosphamide], 24 [benzo(a)pyrene,2-naphthylamine, dimethylnitrosamine] or 48 [diethylstilbestrol], h of exposure in the presence of 3 x 10(6) cells/flask. The degree of conservation and the inducibility of representative oxidative and postoxidative reactions in the novel epithelial cell lines C2.8 and C6, together with their ability to activate a wide spectrum of procarcinogens, offers a means to study the potential of chemicals for inducing DNA damage in short-term genotoxicity testing. In addition the cells may be suitable for analyzing the metabolic disposition of compounds and the multistage process of carcinogenesis.
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PMID:Expression and inducibility of drug-metabolizing enzymes in novel murine liver epithelial cell lines and their ability to activate procarcinogens. 198 92

Benzylselenocyanate (BSC), a novel organoselenium compound, has been found to inhibit azoxymethane (AOM)-induced colon carcinogenesis in rats during initiation. To investigate its mechanism of action, we examined the effects of BSC feeding on the following parameters: (a) metabolism of [14C]AOM to 14CO2 in vivo; (b) metabolic activation of AOM to MAM and of MAM to formic acid and methanol by rat liver microsomes in vitro; and (c) AOM-induced DNA methylation in rat livers and colons. Five-week-old male F344 rats were fed modified (23% corn oil) AIN-76A diets containing 0 (control), 25, or 50 ppm of BSC or benzylthiocyanate (BTC), a sulfur analogue of BSC which does not inhibit the colon carcinogenicity of AOM. After 3 weeks, rats were either sacrificed for the isolation of liver microsomes or were given 15 mg/kg of [14C]AOM s.c. to determine the rate of carcinogen metabolism in vivo. No difference in [14C]AOM metabolism was found between rats fed the BTC diets and those fed the control diet. In contrast, the rate of [14C]AOM metabolism, as determined by exhaled radioactivity, was 2-3 times higher in rats fed the BSC diets. While liver microsomes from rats fed the BTC diets metabolized AOM and MAM at rates not significantly different from those obtained with control liver microsomes, the metabolic activation of AOM as well as of MAM was stimulated severalfold when assayed with liver microsomes from rats fed the BSC diets. An increase in total liver cytochrome P-450 was also observed in the BSC-fed rats. Following the administration of 15 mg/kg AOM, significantly less O6-methylguanine and 7-methylguanine was present in the colon DNA from rats consuming the BSC diets than in rats fed the BTC or control diets. The body weight gains of rats fed the 25- and 50-ppm BSC-containing diets for 3 weeks were less (27 and 43%, respectively) than those of rats fed either the control or BTC-containing diets. These results indicate that dietary BSC significantly induces the hydroxylation of AOM and the oxidation of MAM in rat liver. An increase in the rates of AOM and MAM metabolism in the liver due to enzyme induction by BSC will result in decreased delivery of MAM to the colon via the bloodstream. This will be reflected in decreased DNA alkylation, as observed, and is likely to be a major factor in the inhibition of AOM-induced colon carcinogenesis by BSC.
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PMID:Mechanism of benzylselenocyanate inhibition of azoxymethane-induced colon carcinogenesis in F344 rats. 203 23

The use of the mouse for carcinogenesis bioassays has raised questions regarding the cell of origin of lung tumors. Since a feature of chronic lung injury from aromatic hydrocarbons is an apparent alteration in target cell susceptibility, the present study was designed to test the feasibility of using microdissected pulmonary airways to evaluate the metabolism and cytotoxic response of one of the potential targets of pulmonary carcinogens, the bronchiolar Clara cell. Airways were microdissected from mouse lungs that had been filled by injection of agarose (1%) into the trachea. Ultrastructural integrity of the explants has been maintained for up to 8 h in culture. The cytotoxic response of bronchiolar epithelium in explants incubated with naphthalene (0.5 mM) was identical to the vacuolation and exfoliation observed in bronchioles of mice 24 h after intraperitoneal administration of naphthalene (100 or 300 mg/kg). Pre-incubation of the explants with piperonyl butoxide, a cytochrome P-450 monooxygenase inhibitor, prevented naphthalene-induced cytotoxicity. Naphthalene monooxygenase activity was easily measurable in all levels of airway, including trachea, lobar bronchi, major and minor daughter pathways, and distal bronchioles. No metabolism was detected in lung parenchyma or large vessels. Dihydrodiol and a glutathione adduct derived from 1R, 2S-naphthalene oxide were the sole metabolites detected by HPLC in incubations of airway explants. Formation of a single diastereomeric glutathione conjugate indicated that the metabolic epoxidation of naphthalene was highly stereoselective. Glutathione S-transferase activity was measured in all compartments, with the highest activities in trachea and lowest in distal bronchiole and pulmonary vein. Explants maintained pools of reduced glutathione for up to 4 h in culture. We conclude that microdissected airways have excellent potential for: (1) defining the capability of bronchiolar epithelium to catalyze xenobiotic biotransformation, (2) comparing activity in target and nontarget lung compartments as a means of identifying specific metabolic pathways associated with the cytotoxic response, and (3) use with a variety of species, including nonhuman primates and humans, as a means of providing appropriate data for extrapolation of effects in the intact animal to the human, where bioassay is not possible.
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PMID:Use of microdissected airways to define metabolism and cytotoxicity in murine bronchiolar epithelium. 205 25

The ability of five chemopreventive agents to inhibit 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumors in A/J mice was determined. The carcinogen was administered in the drinking water during 7 weeks (at doses of 9.2 to 3.1 mg/mouse). Three chemopreventive agents: (dose, g/kg diet) ellagic acid (4.0), 2(3)-BHA (5.0), and sulindac (0.13) inhibited the multiplicity of lung adenomas by 52, 88, and 52%, respectively, when compared to NNK controls. beta-Carotene + retinol (2.14 + 0.009), in combination, and selenium (0.0022) were ineffective. NNK was absorbed more rapidly from the duodenum than from the stomach and was metabolized in both tissues. The activation of NNK by alpha-carbon hydroxylation and its deactivation by pyridine N-oxidation was more extensive in the duodenum than in the stomach. Carbonyl reduction of NNK was 10 times higher in the duodenum. Liver microsomes were more active than lung microsomes in the alpha-carbon hydroxylation of NNK, suggesting that some liver isozymes of cytochrome P-450 have a high affinity for NNK. Pyridine N-oxidation was five times more extensive in lung microsomes than in liver microsomes. Collectively, these results demonstrate that NNK given orally to A/J mice provides a suitable model from which to assess the relative activity and mechanisms of action of chemopreventive agents in pulmonary carcinogenesis.
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PMID:Lung tumorigenicity of NNK given orally to A/J mice: its application to chemopreventive efficacy studies. 205 45


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