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)

Male C57/B6 mice were adapted to human diets of British origin that had 3-fold differences in either dietary fibre, fat or beef protein within the normal human range, and were then treated p.o. with 200 mg/kg benzo[a]pyrene (B[a]P) to induce colonic nuclear aberrations. [14C]B[a]P was included in the dose that followed 2 h after a gavage of magnetic PEI microcapsules. Untreated control groups were fed mouse chow or the baseline human diet which was low in all three dietary components (LLL). After the animals were killed at 24 h, large reductions (P less than 0.05) in colonic nuclear aberrations, and alterations to faecally excreted, microcapsule-trapped B[a]P metabolites were found for elevations of all three human diet components. Compared to untreated LLL control, B[a]P treatment gave an 8-fold increase in total nuclear aberrations, which was decreased 2- to 3-fold by increased fibre or fat. HPLC assay of B[a]P metabolites desorbed from microcapsules showed dietary fibre and beef protein to increase B[a]P diols and phenols but almost abolish B[a]P diones, consistent with a shift to enzymatic metabolism from non-specific oxidation. Increased fat considerably altered B[a]P metabolite disposition and microcapsule trapping, and comparison with microcapsules removed from colon contents indicated an altered enterohepatic circulation. Although it was not possible to attribute nuclear aberrations to individual B[a]P metabolites, a possible role of B[a]P diones seemed indicated, this being in line with previous microcapsule studies. These results show that microcapsules and human diets can be used in monitoring modulations of xenobiotic agents linked to mucosal chromosomal damage, with the eventual aim of human microcapsule biomonitoring.
Carcinogenesis 1991 Feb
PMID:Dietary fibre, fat and beef modulation of colonic nuclear aberrations and microcapsule-trapped gastrointestinal metabolites of benzo[a]pyrene-treated C57/B6 mice consuming human diets. 184 18

The metabolism of the phorbol diester [20-3H]12-O-tetradecanoylphorbol-13-acetate [( 3H]TPA) was studied in the back skin of NMRI mice after topical administration of a single tumour-promoting dose, dp. Up to 72 h after administration most of the radioactivity recovered from the skin surface, and from the epidermis and dermis of the treated skin area was unchanged TPA, as determined by silica gel HPLC of extracts obtained from these skin fractions. The major TPA metabolite was less polar than TPA and chromatographed in the range of long-chain TPA-20-acylates. At 72 h, it accounted for about 25, 5 and 30% of total radio-activity extracted from skin surface, epidermis and dermis respectively. Of metabolites more polar than TPA, phorbol-13-acetate (PA) by far predominated over 12-O-tetradecanoylphorbol (TP) in both the epidermis and dermis, and by 72 h its relative amount was 3.9 and 2.4% in these skin fractions. Both phorbol monoesters, PA and TP, were not detected in skin surface extracts. In addition to metabolites, various autoxidation products of TPA were present in small amounts in the extracts from each of the skin fractions. The TPA-20-acylate fraction of metabolites isolated from the extracts of skin fractions at 24 h was separated further into the individual metabolites by the combined use of argentation and reversed-phase HPLC. These individual metabolites were identified by co-chromatography with authentic reference compounds. They were TPA-20-acylates carrying saturated fatty acids (16-26 carbon atoms), cis-mono-unsaturated fatty acids (16-24 carbon atoms), linoleic acid and arachidonic acid. The conjugation of TPA with long-chain fatty acids is the first example of a new route of xenobiotic metabolism in skin. When tested for irritant activity on the mouse ear, TPA-20-acylates were about one to two orders of magnitude less active than TPA. Similarly, when TPA-20-tetradecanoate was tested for tumour-promoting activity on the back skin of NMRI mice over a dose range of dp = 50-200 nmol applied twice weekly according to the computer-assisted standard protocol 16, it was found to be of only intermediate potency as compared to the highly potent tumour promoter TPA. The results of the present investigation indicate that metabolic conjugation of TPA with long-chain fatty acids to yield TPA-20-acylates is another pathway of metabolic deactivation of TPA, thus supporting the hypothesis that TPA itself is the ultimate tumour promoter in mouse skin.
Carcinogenesis 1991 Sep
PMID:Toxicokinetics of tumour promoters of mouse skin. II. Metabolism of the tumour promoter 12-O-tetradecanoylphorbol-13-acetate in mouse skin and biological activities of metabolites. 189 16

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

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 induction of oxidation and conjugation enzymes, the scavenging of carcinogen electrophiles, and the inhibition of aflatoxin B1 (AFB1) activation were examined as possible mechanisms of anti-carcinogenesis by indole-3-carbinol (I3C). Liver microsomal 7-ethoxycoumarin O-deethylase and 7-ethoxyresorufin O-deethylase activities were not induced significantly in rainbow trout fed diets containing 500-2000 ppm I3C for 8 days compared to trout fed the control diet. Furthermore, no detectable changes in the specific contents of cytochrome P-450 isozymes LM2 and LM4b, as measured by Western-blotting and immunoquantitation, were found in liver microsomes following dietary I3C administration. Dietary I3C had no significant effect on liver microsomal uridine diphosphate-glucuronyl-transferase activity, measured using the substrates 1-naphthol and testosterone, or on cytosolic glutathione S-transferase activity, measured using the substrate styrene oxide. The ability of I3C or its acid reaction products (RXM; generated by the reaction of I3C with HCl) to act as scavengers for the direct alkylating agent AFB1-8,9-Cl2 was examined. Addition of I3C or RXM to in vitro incubations did not inhibit the covalent binding of AFB1-8,9-Cl2 to calf thymus DNA. Kinetic analyses of microsome-mediated binding of AFB1 to DNA in vitro indicated that RXM inhibited the metabolic activation of AFB1. RXM increased the apparent Km for the AFB1-DNA binding reaction without changing the associated Vmax; the apparent Km values at 0, 3.5, 35, and 350 microM RXM were 35, 38, 66, and 86 microM for trout liver microsomes. RXM also inhibited the activation of AFB1 by rat liver microsomes, but I3C was not an effective inhibitor against AFB1-DNA binding mediated by either rat or trout liver microsomes. The results of the present study indicate that inhibition of microsome-activated AFB1 binding to DNA by I3C products may be of significant importance in I3C inhibition of hepatocarcinogenesis in trout and other species. The inhibition of carcinogen activation by I3C is contrasted with the mechanism of anti-carcinogenesis by beta-naphthoflavone, which involves induction of xenobiotic metabolizing enzymes.
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PMID:Mechanisms of anti-carcinogenesis by indole-3-carbinol. Studies of enzyme induction, electrophile-scavenging, and inhibition of aflatoxin B1 activation. 210 94

Chemical carcinogenesis is generally recognized as a multistep process consisting of initiation, promotion and progression. Today there is substantial evidence that the process involves reactive species of oxygen, which are generated through enzymic or nonenzymic transformation of xenobiotics and their metabolites, and which can alter nucleic acids, proteins, and lipids, thereby interfering with normal cell growth and differentiation. Most cells possess powerful defense mechanisms against these effects, both in the form of antioxidants acting as free-radical scavengers, and of various enzymes capable of preventing the formation of facilitating the removal of reactive species of oxygen. The present paper is a brief survey of current knowledge concerning these mechanisms. The available information is consistent with the concept that chemical carcinogenesis and its prevention share a common denominator, namely, the metabolic activation of a xenobiotic that can lead, on one hand, to the generation of reactive species of oxygen and thereby cancer initiation, promotion and progression, and, on the other hand, to an induction of antioxidant enzymes that can prevent these effects. The final outcome will depend on the relative impact of the two events. Elucidation of the underlying molecular mechanisms may provide a rationale for devising drugs that enhance resistance against chemical carcinogenesis without themselves being carcinogenic.
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PMID:Nakahara Memorial Lecture. Chemical carcinogenesis and its prevention: is there a common denominator? 213 76

The 4S polycyclic aromatic hydrocarbon (PAH)-binding protein (PBP) is a cytoplasmic protein that binds PAHs with specificity and high affinity. We have used antisera for the PBP and unlabeled peroxidase anti-peroxidase immunohistochemistry to demonstrate its possible localization in cell types known to have xenobiotic metabolizing capabilities. Cellular sites of the PBP in liver, lung and kidney of C57BL/6 and DBA/2 mice were probed. The PBP was visualized in hepatocytes throughout the liver lobule and was not preferentially located in either centrilobular or periportal areas. However, cellular heterogeneity with respect to PBP content was clearly evident in the hepatocyte population. The positive reactivity correlated with substantial levels of benzo[a]pyrene (B[a]P) binding in liver cytosol. In the lung, the PBP was found in the bronchiolar epithelium and the alveolar septa, and was localized in ciliated and non-ciliated Clara and alveolar type II cells as well as in alveolar macrophages. In the kidney, the glomeruli and epithelia of proximal and distal convoluted tubules and collecting ducts were labeled. Staining for the PBP was greatest in the apical region of the pyramid and was localized in the epithelial lining of the collecting ducts. Relatively lower levels of the PBP were detected in the lung and kidney than in the liver. Staining was localized in the cytoplasmic compartment of cells in all tissues examined. Similar immunoreactivities were exhibited in the tissues of both C57BL/6 and DBA/2 mice. Treatment with beta-naphthoflavone (beta NF) altered neither the intensity nor pattern of immunostaining. Furthermore, treatment with beta NF or isosafrole has no effect on the Kd and Bmax of B[a]P binding to liver cytosolic PBP. The results of our experiments demonstrate localization of the PBP to sites of active physiological response to PAH exposure.
Carcinogenesis 1990 Oct
PMID:The 4S polycyclic aromatic hydrocarbon-binding protein: immunohistochemical localization in mice. 220 97

Modern pulmonary toxicology (including lung carcinogenesis) has, to assist its rapid development, constantly incorporated the knowledge obtained through cell and tissue-culture studies. While this has been carried out in rather a passive manner until quite recently, the currently necessary multi-disciplinary approach increasingly requires more active involvement of cell/tissue-culture techniques in this area. Our understanding in this regard is that one of such requirements is to establish a cell-culture system consisting of a single population of possible target cells for certain classes of hazardous inhalants. In addition, such target cells in culture should be able to function in a manner as closely resembling the situation in vivo as possible. In view of the culture techniques presently available, this requirement is probably too ideal to be met immediately. Nevertheless, efforts have been made in the last decade to achieve functioning cultures of Clara cells, type II pneumocytes or small mucus granule cells (SMGC), using undifferentiated cells obtained from animal and human fetuses. This attempt forms a sharp contrast to the usual approach, in that while the latter tries to keep the functions of adult cells in an already differentiated state, the former aims at inducing functional differentiation in undifferentiated cells by manipulating culture conditions. In carrying out these efforts, we have shown clear evidence that the type II pneumocytes and Clara cells induced in vitro are closely cognate and share a common precursor cell in culture, and that SMGC are at a pre-stage of differentiation to Clara cells. We have also shown an induced capacity for xenobiotic activation and conjugation in SMGC in culture. Our next plan is to prove similar activity (of mixed-function oxidase) in Clara cells and type II pneumocytes induced to differentiate in culture.
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PMID:New functional cell-culture approach to pulmonary carcinogenesis and toxicology. 225 74

Compounds of highly variable structure may induce toxic effects and tumours in the respiratory tract following peroral or parenteral administration in experimental animals. Such compounds are used in industrial processes or may be present in the food as contaminants or pesticide residues. This review gives examples of selective metabolism and toxicity of chemicals in different segments of the respiratory tract. Many of these compounds require metabolic activation to exert toxicity. Accordingly, the susceptibility of the respiratory tract to the effects of such agents may be influenced by other compounds modulating the activity of activating xenobiotic metabolizing enzymes. Dietary factors may alter the susceptibility to experimental lung carcinogenesis also via other mechanisms. As concluded from experimental data, the human lung may be exposed to a wide array of potentially toxic compounds present in the diet or the environment. Such exposures may constitute confounding factors in low-risk lung cancer epidemiology.
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PMID:Interactions of xenobiotics in the respiratory tract following non-inhalation routes of exposure. 225 73

Livers of wild English sole (Parophrys vetulus) from polluted waterways and embayments of Puget Sound, Washington, are affected by a spectrum of multiple, co-occurring idiopathic hepatic lesions, including neoplasms, putative preneoplastic foci of cellular alteration, and unique degeneration conditions. Results from a statistical analysis of the patterns of co-occurrence of these lesions in wild English sole indicate that these lesions represent morphologically identifiable steps leading to the development of hepatic neoplasms. This sequence parallels the lesion progression in experimental models of chemically induced liver carcinogenesis in rodents. The hypothesis that these lesions in wild English sole can be caused by exposure to certain xenobiotic hepatotoxic and hepatocarcinogenic compounds in Puget Sound is based on: a) statistical associations between levels of aromatic hydrocarbons (sigma AHs) in sediment and prevalences of these idiopathic liver lesions, b) the contribution of sigma AHs in accounting for the variability in hepatic neoplasm prevalence in a logistic regression model, c) elevated odds ratios for several idiopathic hepatic lesion types in sole from polluted sites in Puget Sound, d) significant correlations between prevalences of idiopathic hepatic lesions and levels of fluorescent metabolites of aromatic compounds (FACs) in bile of English sole, and e) experimental induction of putatively preneoplastic focal lesions in English sole injected with a PAH-enriched fraction of an extract from a contaminated urban sediment from Puget Sound, that were morphologically identical to lesions found in wild English sole from the same site.
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PMID:Overview of studies on liver carcinogenesis in English sole from Puget Sound; evidence for a xenobiotic chemical etiology. I: Pathology and epizootiology. 236 38


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