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)

A review of the literature that pertains to drug biotransformation in human fetal tissues reveals that, in spite of several publications in this comparatively new area of research, only very limited definitive information is currently available. The large majority of the studies performed have dealt with the cytochrome P-450-dependent microsomal mono-oxygenase systems and for several of the common drug metabolising reactions, very little or no data are available at this time. Some of the more important data that have emerged include observations that important bioactivation reactions can be demonstrated in human fetal tissues obtained during the period of late embryogenesis (high susceptibility to chemical dysmorphogenesis) and that the human fetal adrenal gland possesses considerable capacity to catalyse several important oxidation-reduction reactions. From the data available to date, it would appear that, in most instances, the biotransformation of drugs in the human embryo and fetus would not affect maternal plasma concentrations significantly. From the viewpoint of parameters of the pharmacokinetics of parent drug (or other xenobiotic) substrates under steady-state conditions, human fetal drug metabolism probably is of little consequence in most cases, although exceptions may exist. Pharmacokinetic parameters observed after isolated exposure, however, are very likely to be affected, perhaps markedly, in some instances. The demonstrated capacity of human prenatal tissues and cells to generate reactive intermediary metabolites, including those that produce mutations, has attracted the greatest attention recently. This capacity may be associated with extremely important adverse reactions to drugs and other environmental chemicals. Such adverse responses include transplacental mutagenesis, carcinogenesis, dysmorphogenesis, and perhaps several other undesirable effects. Although far from conclusive, the data tend to suggest that humans and subhuman primates may be more vulnerable than the smaller common experimental animals to the toxic effects of foreign organic chemicals during prenatal life. These factors should be weighed whenever exposure of pregnant women to such agents (e.g. via drug administration) is contemplated.
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PMID:Drug metabolism by the human fetus. 699 79

In the search to define the mechanisms by which xenobiotics produce their toxic effects in biological systems, the importance of metabolism data is clear. Although the detection of electrophilic metabolites and reactive intermediates may challenge our analytical technology, the toxic responses manifested by these agents are often obvious. The identification of toxicologically significant minor metabolites may exceed the state of the art in analytical methodology. New advances in technology may provide the needed answers. As we begin to face the significance of activation reactions, particularly in the area of carcinogenesis, it becomes apparent that metabolism to electrophiles that react covalently with DNA, is not the only mechanism by which the tumorigenic response is produced. The production of tumors by nongenotoxic (epigenetic) means is also important. Exposure to high and sustained levels of exposure to a xenobiotic that leads to a perturbation in metabolic, endocrine or physiologic pathways or tissue injury may also produce tumors. Only through investigations which include definitive metabolite identification and quantitation can the mechanism by which these agents exert their toxicity be identified. The ramification of dose response relationships for genotoxic and nongenotoxic carcinogens will be presented to demonstrate the impact of metabolite identification in quantitative risk estimation.
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PMID:The importance of metabolite identification in quantitative risk estimation. 716 53

Cytotoxic and cell-transforming activities of the three fungicides, captan, captafol and folpet, have been studied in an experimental in vitro model by exposing BALB/c 3T3 cells to the chemicals with or without S-9 mix-induced bioactivation. Cytotoxicity of the three compounds was reduced in the presence of the metabolizing system. Each assayed pesticide displayed cell-transforming ability in the presence of the metabolizing system. The relative efficiency was: captafol > captan > folpet. Cell transformation was considered to be due to carcinogenesis-promoting activity. These data, obtained in a medium-term (6-8 weeks) experimental model, contribute to a better understanding of the action of the three pesticides in the multistep carcinogenesis process and provide more information concerning the oncogenic risk of these xenobiotic compounds for humans.
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PMID:Transformation of BALB/c 3T3 cells in vitro by the fungicides captan, captafol and folpet. 749 13

The effect of caloric restriction (CR) on xenobiotic metabolizing enzyme activities results in alterations in the metabolic activation of chemical carcinogens, with a resultant impact on DNA-carcinogen adduct formation and DNA repair. Using aflatoxin B1 (AFB1) and benzo[a]pyrene (BP) as model carcinogens, we studied the effect of CR on the metabolic activation of these carcinogens and carcinogen-induced DNA damage and repair in terms of AFB1-DNA and BP-DNA adduct formation and removal. Male Fischer 344 rats fed calorie restricted diets (60% of the food consumption for ad libitum-fed rats) showed a reduction in the metabolic activation of AFB1 and decrease in both the in vitro and in vivo AFB1-DNA adduct formation. However, CR increased the activity of BP metabolizing enzymes resulting in an enhancement of BP-DNA adduct formation. Our results indicate that the effect of CR on metabolic activation of xenobiotics is dependent upon the selected xenobiotic metabolizing enzymes whose activities may be significantly altered by CR, and upon the nature of the chemical carcinogens which exert different structure-activity relationships during the process of chemically induced carcinogenesis.
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PMID:Effect of caloric restriction on the metabolic activation of xenobiotics. 750 59

Induction of cellular detoxification enzymes can increase detoxification of carcinogens and reduce carcinogen-induced mutagenesis and tumorigenesis. To determine if the dietary anticarcinogen ellagic acid induced enzymes which detoxify xenobiotics and carcinogens, we examined the effect of ellagic acid on the expression of the phase II detoxification enzyme NAD(P)H:quinone reductase (QR). QR is induced by xenobiotics and antioxidants interacting with the xenobiotic responsive and antioxidant responsive elements of the 5' regulatory region of the QR gene. Ellagic acid is structurally related to the antioxidants which induce QR and we proposed that ellagic acid would induce QR expression through activation of the antioxidant responsive element of the QR gene. Rats fed ellagic acid demonstrated a 9-fold increase in hepatic and a 2-fold increase in pulmonary QR activity, associated with an 8-fold increase in hepatic QR mRNA. To determine if this increase in QR mRNA was due to activation of the antioxidant responsive element, transient transfection studies were performed with plasmid constructs containing various portions of the 5' regulatory region of the rat QR gene. These transfection studies confirmed that ellagic acid induces transcription of the QR gene and demonstrated that this induction is mediated through the antioxidant responsive element of the QR gene.
Carcinogenesis 1994 Sep
PMID:Ellagic acid induces NAD(P)H:quinone reductase through activation of the antioxidant responsive element of the rat NAD(P)H:quinone reductase gene. 752 86

Treatment of cultures of spontaneously immortalized human epidermal cells with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) sensitized them to carcinogen toxicity. While the tryptophan pyrolysis product 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and the mycotoxin sterigmatocystin were highly toxic to the cultures at moderate concentration (1 microgram/ml), the potency of each agent was increased > or = 10-fold in the presence of TCDD. A toxicity increase was also evident in the several-fold stimulation by TCDD of protein and DNA adducts formed by Trp-P-1. In contrast, the cells were insensitive to toxicity from 3-amino-1-methyl-5H-pyrido[4,3-b]indole. DNA damage mediated by Trp-P-1 was capable of producing inheritable effects, as judged by the induction of hprt mutants in a TCDD-stimulated fashion. Northern blotting showed that TCDD strongly stimulated expression of P4501A1 and 1B1 in the cells, enzymes important for xenobiotic metabolism. These findings demonstrate the potential usefulness of SIK cultures as a model for studying keratinocyte responses to carcinogens activated by TCDD-induced cytochromes P450.
Carcinogenesis 1995 Sep
PMID:2,3,7,8-Tetrachlorodibenzo-p-dioxin sensitization of cultured human epidermal cells to carcinogenic heterocyclic amine toxicity. 755 73

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is a major pungent and irritating ingredient of hot chilli peppers, which are frequently consumed as spices. This dietary phytochemical has been found to interact with microsomal xenobiotic metabolizing enzymes in rodents. Capsaicin and its saturated analog dihydrocapsaicin (trans-8-methyl-N-vanillyl-6-nonanamide) have been proposed to inactivate cytochrome P-450 HE1 by irreversibly binding to the active sites of the enzyme. Besides cytochrome P-450 HE1, other isoforms of the P-450 superfamily were also reported to be inhibited by capsaicin. The inhibition by capsaicin of microsomal monooxygenases involved in carcinogen activation implies its chemopreventive potential. As part of a program to investigate chemoprotective properties of capsaicin we initially determined the effect of capsaicin on vinyl carbamate (VC)- and N-nitrosodimethylamine (NDMA)-induced mutagenesis in Salmonella typhimurium TA100. Capsaicin (0.42 mM) attenuated the bacterial mutagenicity of VC and NDMA by 50% and 42% respectively. Diallyl sulfide, a thioether found in garlic with selective P-450 HE1 inhibitory activity, also lessened the mutagenicity of the above carcinogens in a concentration-dependent manner. The suppression of VC- and NDMA-induced mutagenesis by capsaicin and diallyl sulfide correlated with their inhibition of P-450 IIE1-mediated p-nitrophenol hydroxylation and NDMA N-demethylation. Pretreatment of female ICR mice with a topical dose of capsaicin lowered the average number of VC-induced skin tumors by 62% at 22 weeks after promotion. A similar degree of protection was attained with oral administration of diallyl sulfide before carcinogen treatment. The results of this study suggest that capsaicin and diallyl sulfide suppress VC- and NDMA-induced mutagenesis or tumorigenesis in part through inhibition of the cytochrome P-450 IIE1 isoform responsible for activation of these carcinogens.
Carcinogenesis 1995 Oct
PMID:Chemoprotective effects of capsaicin and diallyl sulfide against mutagenesis or tumorigenesis by vinyl carbamate and N-nitrosodimethylamine. 758 53

Experimental carcinogenicity studies focus on identification of single carcinogens. Humans, however, appear exposed to a variety of low doses of carcinogens. Furthermore, few chemical entities are carcinogenic or toxic per se, but require metabolic activation to form ultimate carcinogens or toxins. In contrast to experimental animals, humans show considerable difference in genetic properties. In that situation it is particularly important to estimate individual capability for metabolic activation. To an increasing extent, activation includes formation of toxic oxygen metabolites. Particular targets for activated species are DNA and lipids; in particular low-density lipoproteins (LDL). Modifications of DNA are important for initiating the multistep process of carcinogenesis, in particular if oncogenes are activated or if tumor supressor genes are inactivated. Such DNA modification can be identical regardless of the reactive specimens being a xenobiotic or an oxygen species. Modification of LDL can start the process of atherosclerosis by transforming macrophages into foam cells, deposited as fatty streaks in the arterial wall. Biomarkers for activation capacity of xenobiotics include the use of prototype substrates and molecular techniques to determine genetic polymorphisms. Oxidative DNA modification can be measured from urinary excretion of oxidatively modified deoxynucleosides, particularly guanosine. Future efforts have to include individual measurements in order to improve the 'resolution' of molecular epidemiological approaches.
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PMID:Early biochemical markers of effects: enzyme induction, oncogene activation and markers of oxidative damage. 763 23

Skin is a major target organ for many experimental carcinogens that exist in our environment and the majority of previous carcinogenicity studies have utilised animal derived models. In view of the fact, that many of these environmental chemicals exhibit species- and tissue-specific metabolism, a human skin tissue derived model would be a distinct advantage. Squamous epithelial carcinoma is a predominant form of skin cancer in man and, in theory, human epidermal keratinocytes present an appropriate target cell to employ as an in vitro system to study epidermal carcinogenesis. This report demonstrates the valuable potential of human keratinocyte cultures as a suitable model for mechanistic studies on factors which may influence DNA damage and, hence, the subsequent development of cancer in human epidermis. Keratinocytes were serially cultivated from adult human skin samples and maintained in culture for at least 3 passages. Tertiary cultures, isolated from 3 separate individuals, were exposed to the direct-acting experimental carcinogen, methyl methanesulphonate (CAS No. 66-27-3), and benzo[a]pyrene (CAS No. 50-32-8), which requires metabolic activation. DNA repair was assessed by a quantitative autoradiographic technique. Methyl methanesulphonate and benzo[a]pyrene both elicited a dose-related increase in unscheduled DNA synthesis in cultures prepared from each individual. Inter-individual variation in the response was observed for each chemical, but this was greater in the case of benzo[a]pyrene, which indicates inter-individual variation in both xenobiotic metabolism activity and DNA repair capacity.
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PMID:Chemically-induced unscheduled DNA synthesis in cultures of adult human epidermal keratinocytes. 768 Apr 14

Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is a primary pungent and irritating principle present in chilies and red peppers which are widely used as spices. Because of its selective effects on the functions of a defined subpopulation of sensory neurons, capsaicin is currently used as a versatile tool for the study of pain mechanisms and also for pharmacotherapy to treat several pain disorders. Considering the frequent consumption of capsaicin as a food additive and its current medicinal use, correct assessment of hazardous effects of this compound is important. Mutagenic and carcinogenic activities of capsaicin and chili extracts have been studied, but results are conflicting. Mammalian metabolism of capsaicin has been also reported. Capsaicin appears to interact with xenobiotic metabolizing enzymes, particularly microsomal cytochrome P450-dependent monooxygenases which are involved in activation as well as detoxification of various chemical carcinogens and mutagens. Recent studies have shown that hepatic cytochrome P450 2E1 catalyzes the conversion of capsaicin to reactive species such as the phenoxy radical intermediate capable of covalently binding to the active site of the enzyme as well as tissue macromolecules. While covalent modification of protein and nucleic acids leads to toxicity including necrosis, mutagenesis, and carcinogenesis, suicidal inhibition of microsomal cytochrome P450 may prohibit further activation of capsaicin and also of other toxic xenobiotics. Results from recent studies indicate that capsaicin possesses the chemoprotective activity against some chemical carcinogens and mutagens.
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PMID:Capsaicin, a double-edged sword: toxicity, metabolism, and chemopreventive potential. 774 93


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