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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is convincing evidence that cellular prooxidant states--that is, increased concentrations of active oxygen and organic peroxides and radicals--can promote initiated cells to neoplastic growth. Prooxidant states can be caused by different classes of agents, including hyperbaric oxygen, radiation, xenobiotic metabolites and Fenton-type reagents, modulators of the cytochrome P-450 electron-transport chain, peroxisome proliferators, inhibitors of the antioxidant defense, and membrane-active agents. Many of these agents are promoters or complete carcinogens. They cause chromosomal damage by indirect action, but the role of this damage in carcinogenesis remains unclear. Prooxidant states can be prevented or suppressed by the enzymes of the cellular antioxidant defense and low molecular weight scavenger molecules, and many antioxidants are antipromoters and anticarcinogens. Finally, prooxidant states may modulate the expression of a family of prooxidant genes, which are related to cell growth and differentiation, by inducing alterations in DNA structure or by epigenetic mechanisms, for example, by polyadenosine diphosphate-ribosylation of chromosomal proteins.
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PMID:Prooxidant states and tumor promotion. 298 33

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

The concentration in pancreatic tissue and the total pancreatic content of three xenobiotic metabolising enzymes has been determined in two models of experimental pancreatic growth namely, cholecystokinin-octapeptide injections and soy flour feeding. No significant change in pancreatic concentrations of benzo(a)pyrene hydroxylase or glucuronyl transferase was detected. In both models of pancreatic growth, however, the concentration of glutathione-S-transferase was significantly reduced. It is possible that the reduction in this enzyme may be of some importance in determining the susceptibility of the pancreas to carcinogenesis observed with long term soy flour feeding.
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PMID:Effect of experimental pancreatic growth on the content of xenobiotic-metabolising enzymes in the pancreas. 312 55

The metabolism of acetylaminofluorene (AAF) in human hepatocyte cultures from different donors was investigated for a four-log concentration range (500, 50, 5.0 and 0.5 microM) or at 3, 8 and 24 h at 500 microM. The metabolite profile was dependent on the concentration to which the cells were exposed. The hepatocyte cultures varied in the degree to which they metabolized AAF predominantly because of different levels of deacetylation. Ring-hydroxylation was the predominant pathway for AAF metabolism at low concentrations (5.0 and 0.5 microM) but saturated in three of four human cases at high concentrations of AAF; N-hydroxylation did not appear to become saturated. Human hepatocytes catalyzed the covalent binding of AAF metabolites to their DNA. A linear increase in DNA binding was observed when increasing concentrations of AAF were added to hepatocyte cultures; however, the increase in AAF metabolites binding to DNA was not proportional to the dose. While the concentration of AAF in the media was increased over a four-log range, both the production of N-hydroxy AAF and binding of metabolites to hepatocellular DNA increased over approximately a three-log range. These results with cultured human hepatocytes indicate that the pathways of AAF metabolism are qualitatively similar to those identified in experiments with rat hepatocytes as well as experiments conducted in vivo with human subjects. These studies confirm that the cultured human hepatocyte is a useful model for the investigation of human xenobiotic metabolism and indicate that the concentration of the xenobiotic used in the experiments is an important determinant of the metabolitic profile produced.
Carcinogenesis 1988 Oct
PMID:Metabolism of acetylaminofluorene in primary cultures of human hepatocytes: dose-response over a four-log range. 316 62

We investigated the possibility that variations of the metabolism of xenobiotic compounds might be involved in the process of bladder carcinogenesis, by studying activation reactions (phase I) and detoxification reactions (phase II) of xenobiotic compounds in a group of patients with transitional cell carcinoma of the bladder and in a group of controls hospitalised with other diseases. As an indirect estimate of activating reactions (phase I) we measured cortisol hydroxylation, expressed as the ratio between urinary 6-beta-OH-cortisol and 17-OH-corticosteroids. Cortisol hydroxylation was not increased in the group of patients when compared with controls. The variations of phase II conjugating enzymes were followed indirectly by administering paracetamol and measuring the urinary excretion of its main metabolites over a period of 12 h. The variations in the metabolic conjugation of paracetamol were expressed as a percentage of each metabolite, or of unmodified paracetamol excreted in the urine, or as the ratio between a given metabolite and unmodified paracetamol. The data were analyzed with a logistic regression model, analysing the effects of possible confounding variables such as age, smoking, alcohol, blood nitrogen, blood creatinine, glutamic-pyruvic (SGPT), glutamic-oxalacetic transaminases (SGOT) and percent recovery of paracetamol in the urine. Statistical analysis showed that the excretion of mercapturate derivatives of paracetamol was significantly increased in the group of patients. The levels of glucuronic, sulphate and cysteine metabolites were not varied significantly. Since mercapturate derivatives are formed as a consequence of the formation of short-lived metabolites of paracetamol which react with protein, nucleic acids or glutathione, the increased excretion of mercapturic acid derivatives in cancer patients might be an indication of a higher capability of forming reactive molecular species from xenobiotic compounds. We suggest that this factor might play a role in the induction of bladder cancer.
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PMID:Variations of cortisol hydroxylation and paracetamol metabolism in patients with bladder carcinoma. 320 22

Some highlights in the development of our knowledge about carcinogens as etiological agents for cancer are reviewed briefly. Advances during the past 20 years relating to metabolic activation with the genesis of reactive metabolites, molecular targets and their interactions with activated carcinogens, oncogenes as molecular targets and the dependence on cell proliferation, all relating to the initiation process, are reviewed. Critical to initiation is the new phenotype in the initiated cell, known only in one instance, the rat liver, in which the characteristic change is one of resistance to many xenobiotic influences. The need for clonal expansion of initiated cells as essential for carcinogenic effects is discussed. Differential inhibition has been shown as a dominant mechanistic pattern in the liver. In other systems, the manner in which clonal expansion is achieved is not evident. The need for studies of the processes involved in carcinogenesis, as well as the agents, is emphasized, in view of the continuing validity of the cell concept as the key to integrating the increasingly large volume of data from the molecular with the biological.
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PMID:Possible etiologic mechanisms in chemical carcinogenesis. 331 67

To examine the transcriptional regulation of the human cytochrome P450IA1 gene, a 3574 bp fragment containing 1140 bp of 5' flanking sequences, exon 1 (leader information only), intron 1, and the leader sequences from exon 2, was cloned upstream of the reporter gene, chloramphenicol acetyltransferase, and used to transfect the human hepatoma cell line, HepG2. In transient expression assays, treatment of the transfected cells with 3-methylcholanthrene, benzo[a]pyrene or 2,3,7,8-tetrachlorodibenzofuran was shown to induce the expression of chloramphenicol acetyltransferase 10-fold. Previous studies by other investigators have identified a xenobiotic responsive element at greater than 800 bp 5' to the cap site in the mouse and rat cytochrome P450IA1 gene. In the current report, deletion of sequences from the 5' side of the P450IA1 fragment, as well as internal deletions, were used to identify at least three additional regulatory elements. A second positive, 3-methylcholanthrene responsive element was localized to sequences between -49 and -560 in addition to confirming the location of a similar element between -831 and -1140. These elements flank a potent negative regulatory element that has been conserved between the rat, mouse and human P450IA1 genes and also exhibits significant sequence identity with one of the negative control elements of the human c-Ha-ras1 proto-oncogene. Deletion of the negative control element clearly demonstrated that the fragments containing xenobiotic responsive elements also possess positive, constitutive control activity. A fourth element located within intron 1 was shown to potentiate the activity of 3-methylcholanthrene when the cells were treated simultaneously with the glucocorticoid agonist, dexamethasone.
Carcinogenesis 1988 Sep
PMID:Identification of multiple regulatory elements on the human cytochrome P450IA1 gene. 340 63

The putative ultraviolet (u.v.) carcinogenesis of cutaneous melanoma bears sufficient inconsistencies as to seriously challenge this theory. A more attractive hypothesis is the incrimination of a hitherto unknown chemical xenobiotic. This hypothesis explains the dramatic increase in incidence rates in most affluent countries during the last two or three decades. It also explains the particular risk of populations of high socio-economic status and the increased risk of indoor workers. It finally explains the urban-rural and coastal-inland trends observed in many countries with high incidence rates.
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PMID:Melanoma of the skin is not caused by ultraviolet radiation but by a chemical xenobiotic. 364 22

This study was designed to test further the hypothesis that the special biochemical pattern seen in hepatocyte nodules during liver carcinogenesis could be of fundamental importance in their selective metabolism of one carcinogenic xenobiotic, 2-AAF, as related to their resistance to xenobiotics. Nodules of a certain stage were induced using the resistant hepatocyte model. The metabolism of a single small dose of 2-AAF in hepatocyte nodules in comparison to normal liver was studied at different time intervals up to 30 h. The levels of free 2-AAF in nodules and in normal liver were approximately the same over the whole time period. However, the nodules showed a large decrease in the binding of 2-AAF to DNA, RNA and proteins as well as in the metabolic conversion to hydroxylated forms, both free and conjugated with glucuronic acid. The patterns of metabolic conversion to metabolites and of conjugation of the metabolites are in harmony with the known biochemical patterns in nodules, a decrease in phase I components involved in the metabolism of carcinogens and other xenobiotics and an increase in most phase II components involved in conjugation and detoxification.
Carcinogenesis 1986 Apr
PMID:The pattern of metabolism of 2-acetylaminofluorene in carcinogen-induced hepatocyte nodules in comparison to normal liver. 369 85

In a previous paper we reported on the influence of sex and pituitary hormones on the selection of diethylnitrosamine-initiated, enzyme-altered cells by 0.02% (w/w) 2-acetylaminofluorene (2-AAF) and partial hepatectomy in the resistant hepatocyte model (RH-model). The islands of enzyme-altered cells in this model grew faster in male than in female rat liver and the growth rate was markedly decreased in male rats bearing ectopic pituitary grafts during the 2-AAF selection period. Male rats are also generally more susceptible to 2-AAF carcinogenesis than female rats. In order to investigate whether the sex differentiated response to 2-AAF selection and 2-AAF carcinogenesis might be due to pituitary control of xenobiotic metabolism, as previously shown for rat liver metabolism of steroid hormones, we have studied the influence of age, sex and pituitary hormones on the cytochrome P-450-mediated hydroxylations of 2-AAF and benzo[a]pyrene (B[a]P), O-deethylation of 7-ethoxyresorufin and the metabolism of 4-androstene-3,17-dione (androstenedione) in rat liver microsomes. Microsomes from prepubertal rats had a generally higher capacity to metabolize the xenobiotic compounds whereas the capacity for androstenedione hydroxylation was low. In adult rats pronounced sex differences and a marked influence of pituitary hormones were observed in the microsomal formation of several 2-AAF metabolites as well as in B[a]P and androstenedione metabolism. The results clearly show that at least the oxidative pathways of 2-AAF and B[a]P metabolism are controlled by pituitary hormones in a similar way to the rat liver metabolism of steroids. These data do not, however, provide any explanation for the previously mentioned sex differences in the RH-model or in 2-AAF carcinogenesis. We therefore suggest that the pituitary regulation of other pathways of 2-AAF metabolism must be considered in order to clarify the biochemical background behind sexually differentiated 2-AAF carcinogenesis in rat liver.
Carcinogenesis 1986 Apr
PMID:Pituitary regulation of cytochrome P-450-mediated metabolism of steroids and xenobiotics in rat liver microsomes. 369 89


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