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)

The concentration-, time- and route-dependent effects of ethanol co-administration on tumorigenesis by N-nitrosodimethylamine (NDMA) were characterized in strain A male mice. With drinking-water administration, 1% ethanol was as effective as 5 or 10% in effecting a 4-fold enhancement of lung tumorigenesis by 5 p.p.m. NDMA. In a study of cumulative effects over time, 10% ethanol given with 1 p.p.m. NDMA resulted in a progressive increase in lung tumors from 16 to 72 weeks. In addition, at 72 weeks, the ethanol co-treatment resulted in a significant increase in kidney adenomas and possibly in vascular tumors of liver. A single i.g. dose of 5 mg/kg NDMA was significantly tumorigenic for lung, and the effect was dose-dependently increased by inclusion of ethanol, for up to a 9-fold enhancement with 20% ethanol. When 10% ethanol was given in the drinking water while NDMA was administered as 20 1 mg/kg doses by other routes--i.g., i.p., s.c. or i.v.--the ethanol treatment was without effect on lung tumor numbers. Collectively, the results provide strong support for inhibition of hepatic first-pass clearance of NDMA by cytochrome P450 2E1 as the mechanism of ethanol's effect, and suggest that several other possible mechanisms are unlikely. They also illustrate that a moderate dose of ethanol cumulatively increases tumor risk from a low dose of NDMA given over most of the lifetime of the animal.
Carcinogenesis 1992 Nov
PMID:Characterization of ethanol's enhancement of tumorigenesis by N-nitrosodimethylamine in mice. 142 83

Disulfiram and its breakdown product diethyldithiocarbamate (DDTC) have been investigated for their potential to protect against chemically-induced toxicity and carcinogenesis because of their inhibitory effects on cytochrome P450 2E1. We used DDTC in order to examine the role that cytochrome P450 2E1 plays in the bioactivation of beta,beta'-iminodipropionitrile (IDPN) and 2,6-dichlorobenzonitrile (dichlobenil), resulting in site-specific olfactory lesions in the Long-Evans rat and C57B1 mouse. DDTC and disulfiram themselves produced olfactory mucosal lesions in the rat, whereas DDTC protected against the olfactory toxic effects of dichlobenil in the mouse. A dose-response study revealed that approximately twice the dose of DDTC was required in mice to cause the same olfactory toxic effects seen in the rat. A study to determine the catalytic activity of P450 2E1 by p-nitrophenol (PNP) hydroxylation indicated that the Long-Evans rat nasal mucosa is 2.4 times more active than the C57B1 mouse, which may account for the greater susceptibility of the rat to the olfactory toxic effects of DDTC. PNP hydroxylation assays confirmed that DDTC decreased P450 2E1 activity in both the rat and mouse liver and nasal mucosa. Whereas the results of the mouse study strengthen the hypothesis that dichlobenil is bioactivated to a toxic metabolite by cytochrome P450 2E1 in the C57B1 mouse, rats pretreated with a marginally toxic dose of DDTC prior to the administration of IDPN displayed olfactory mucosal damage, indicating that an alternative or additional pathway may be operative in the metabolism of IDPN and/or DDTC.
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PMID:Olfactory toxicity of diethyldithiocarbamate (DDTC) and disulfiram and the protective effect of DDTC against the olfactory toxicity of dichlobenil. 772 93

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

The clastogenicity of tamoxifen and toremifene was tested in six human lymphoblastoid cell lines each expressing increased monooxygenase activity associated with a specific transfected human cytochrome P450 cDNA (CYP1A1, CYP1A2, CYP2D6, CYP2E1 or CYP3A4). The chemicals were also tested in a cell line (MCL-5) expressing elevated native CYP1A1 and containing transfected CYP1A2, CYP2A6, CYP2E1 and CYP3A4 and epoxide hydrolase, and in a cell line containing only the viral vector (Ho1). Dose-related increases in micronuclei were observed when cells expressing 2E1, 3A4, 2D6 or MCL-5 cells were exposed to tamoxifen. The positive responses in the cell lines were in the order MCL-5 > 2E1 > 3A4 > 2D6. Toremifene also gave positive results with 2E1, 3A4 and MCL-5 cells, although the responses were less marked and the positive effects required higher doses than with tamoxifen. A synthesized epoxide of tamoxifen was also tested in these cell lines and produced similar increases in the incidences of micronucleated cells. The increases in the responses observed with the epoxide were greater than with tamoxifen or toremifene. The P450 isoenzyme activities in these cells were in a range similar to those of human tumour-derived cell lines. Microsomes (1A1, 2A2, 2A6, 2B6, 2E1, 3A4 and 2D6) from these cells all metabolized tamoxifen. The major metabolite detected by HPLC was N-desmethyltamoxifen, and 4-hydroxytamoxifen was also detected in cells with cytochrome P450 2E1 and 2D6. These results are consistent with the following conclusions. (1) Tamoxifen requires metabolic activation to DNA-reactive species by specific CYP monooxygenases in order to exert its genotoxic effects. (2) The positive clastogenic effects elicited in lymphoblastoid cells by tamoxifen epoxide suggest that the genotoxic (and possibly the carcinogenic) effects of tamoxifen may be due to one or more epoxide metabolites that are generated intracellularly, probably in close proximity to the nucleus. (3) Tamoxifen is more genotoxic than toremifene.
Carcinogenesis 1994 Jan
PMID:Genotoxicity of tamoxifen, tamoxifen epoxide and toremifene in human lymphoblastoid cells containing human cytochrome P450s. 829 48

The metabolism of N-nitrosodipropylamine (NDPA), N-nitrosodibutylamine (NDBA) and N-nitroso-n-butyl-n-propylamine (NBPA) was investigated in vitro using liver microsomes and purified isoforms of cytochrome P450 in a reconstituted system. Liver microsomes were prepared from rats pretreated with phenobarbital (PB), pyridine (PYR), beta-naphthoflavone (BNF), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), clofibrate (CLO) or from untreated rats. The purified cytochrome P450s used in the reconstituted system were rat 1A1 and 2B1 and rabbit 2E1. The rates of metabolism and the product profiles for NDPA, NDBA and NBPA changed significantly depending on the pretreatment of the rats or the identity of the purified cytochrome P450 isoforms. Induction by PB dramatically increased cleavage of NDPA, NDBA and NBPA at C-N bonds, leading to substantial increases in formation of the respective aldehydes and the overall metabolic rates. Microsomes from PYR-pretreated rats exhibited increased activities for formation of formaldehyde and propionaldehyde from NDPA and NBPA. Microsomes from BHT-pretreated rats showed a slight increase in activity for N-dealkylation of NDBA and BNPA. Treatment with BHA decreased the overall metabolism of NDBA, but slightly increased N-dealkylation of NBPA. Microsomal metabolism of NDPA, NDBA and NBPA was decreased by pretreatment with BNF and CLO. Results from studies using the reconstituted system with purified cytochrome P450 isoforms demonstrated that cytochrome P450 2B1 specifically catalyzed alpha-hydroxylation of these three long chain nitrosamines with high activity. Cytochrome P450 2E1 catalyzed formation of formaldehyde and propionaldehyde from NDPA and NBPA, but did not catalyze formation of acetaldehyde or butyraldehyde. Cytochrome P450 1A1 exhibited no activity for metabolism of NDPA, NDBA and NBPA. The contributions of cytochrome P450 2B1 and 2E1 to N-dealkylation reactions were determined using inhibitory monoclonal antibodies (mAb). With microsomes from PB-pretreated rats, inhibition by mAb-2B1 indicated a 62% contribution by cytochrome P450 2B1 to debutylation of NDBA and 65% to depropylation of NDPA. In microsomes from PYR-pretreated rats inhibition by mAbs also showed a role for cytochrome P450 2E1 in depropylation of NDPA. These studies provide a better understanding of the role of various forms of cytochrome P450 in metabolic activation of these long chain N-nitrosodialkylamines to potentially toxic, mutagenic and carcinogenic intermediates.
Carcinogenesis 1996 Apr
PMID:Identification of the cytochrome P450 isozymes involved in the metabolism of N-nitrosodipropyl-,N-nitrosodibutyl- and N-nitroso-n-butyl-n-propylamine. 862 99

Vinyl chloride (VC), a known human and rodent carcinogen, is metabolically activated by cytochrome P450 to chloroethylene oxide (CEO), which can rearrange to chloroacetaldehyde (CAA) or undergo hydrolysis. To further understand the roles of CEO and CAA in VC mutagenesis, the types and frequencies of mutations induced at the hypoxanthine (guanine) phosphoribosyl-transferase (hprt) locus were examined in a human B-lymphoblastoid line constitutively expressing human cytochrome P450 2E1 (H2E1 cells). VC was toxic and mutagenic to H2E1 cells as a function of incubation time; exposure to 7.5% VC in air resulted in 75% survival and an hprt mutant frequency of 42 x 10(-6) after 48 h, compared to 5.7 +/- 2.7 x 10(-6) for unexposed cells. The exposure of H2E1 cells to 0.8 to 15.0% VC in air produced similar mutant frequencies without a clear dose-response relationship, suggesting saturation of metabolic activation. Both CEO and CAA exhibited dose-dependent increases in cell killing and mutant frequency in H2E1 cells. Treatment with 16 microM CEO for 24 h resulted in 75% survival and an induced mutant frequency of 23 x 10(-6), while 16 microM CAA produced 5% survival and an induced mutant frequency of 20 x 10(-6). Structural alterations at the hprt locus in independent thioguanine-resistant clones were examined by Southern blot analysis of Pst I-digested DNA with a full-length human hprt cDNA probe. Ten percent (5/50) of VC-induced and 18% (7/38) of CEO-induced mutants showed detectable deletions, compared with 45% (9/20) of CAA-induced mutants. Thus, VC and CEO displayed similar toxicity/mutation profiles and a similar frequency of large deletions, whereas CAA displayed greater toxicity and a larger frequency of deletion mutations. These results suggest that the majority of mutations induced by VC occur through its metabolite, CEO.
Carcinogenesis 1997 Jan
PMID:Mutagenicity of vinyl chloride and its reactive metabolites, chloroethylene oxide and chloroacetaldehyde, in a metabolically competent human B-lymphoblastoid line. 905 86

The alkylation of DNA, RNA and protein by labeled metabolites of [alpha-14C]nitrosodimethylamine (NDMA), [alpha-14C]nitrosodipropylamine (NDPA) and [alpha-14C]nitrosodibutylamine (NDBA) was determined as a measure of the metabolic activation of these nitrosamine carcinogens in vitro using microsomes prepared from freshly isolated rat hepatocytes as well as in intact cells using primary cultured rat hepatocytes. The abilities of these nitrosodialkylamines to alkylate cellular macromolecules were significantly affected by pretreatment of rats with inducers of cytochrome P450 and were related to the specific activities of cytochrome P450 2B1 or 2E1 in rat hepatocytes. Pretreatment of rats with phenobarbital (PB) substantially increased the catalytic activity of pentoxyresorufin (PR) O-depentylase, an activity catalyzed by cytochrome P450 2B1, in rat hepatocytes. The increase in the PR O-depentylase activity was associated with a significant increase in the alkylation of DNA or RNA by NDPA, and in alkylation by NDBA, particularly of proteins. However, induction of cytochrome P450 2B1 resulted in a significant decrease in alkylation of cellular macromolecules by NDMA in all cases. In contrast, enhancement of the catalytic activity of the p-nitrophenol (pNP) hydroxylase (P450 2E1) due to pretreatment of rats with pyridine (PYR) resulted in a significant increase in the alkylation of cellular DNA by NDMA. The induction of cytochrome P450 2E1 also increased the alkylation of DNA and RNA by NDPA, but to a lesser extent. Inhibition studies using the chemical inhibitors orphenadrine (OP) and diethyldithiocarbamate (DDC), which are specific for cytochromes P450 2B1 and 2E1, respectively, indicated that cytochrome P450 2B1 was not involved in the metabolic activation of NDMA and that cytochrome P450 2E1 was not responsible for the bioactivation of NDBA. The results presented here demonstrate the substrate specificity and important role of cytochromes P450 2B1 and 2E1 in the bioactivation of nitrosodialkylamines, and suggest that multiple mechanisms may be involved in carcinogenesis induced by nitrosodialkylamines.
Carcinogenesis 1997 Apr
PMID:Alkylation of cellular macromolecules and target specificity of carcinogenic nitrosodialkylamines: metabolic activation by cytochromes P450 2B1 and 2E1. 911 Dec 18

The chemopreventive efficacy of N-acetyl-L-cysteine (NAC), anethole trithione, miconazole and phenethylisothiocyanate (PEITC), each of which would be expected to alter carcinogen metabolism, was examined in the dimethylbenzanthracene (DMBA) mammary carcinogenesis model. In this protocol, animals were exposed to non-toxic doses of the chemopreventives in the diet beginning 7 days prior to DMBA administration and then continuously throughout the duration of the assay (100 days post carcinogen). Miconazole, an antifungal agent with relatively broad inhibitory activity toward a variety of cytochromes P450, increased mammary tumor latency, decreased tumor incidence at the highest dose and decreased tumor multiplicity up to 60%. Anethole trithione, a substituted dithiolthione and an analog of the relatively broad-spectrum chemopreventive oltipraz, was administered in the diet and significantly inhibited mammary cancer multiplicity but not cancer incidence. NAC, an antimucolytic agent, failed to inhibit DMBA-induced mammary tumorigenesis. Surprisingly, treatment with DMBA plus PEITC, a potent inhibitor of cytochrome P450 2E1, actually increased the multiplicity of tumors relative to that observed with DMBA alone.
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PMID:Chemopreventive efficacy of anethole trithione, N-acetyl-L-cysteine, miconazole and phenethylisothiocyanate in the DMBA-induced rat mammary cancer model. 921 29

Although the liver is the major organ responsible for ethanol metabolism, such metabolism also occurs in the gastrointestinal (GI) tract. However, compared to the liver, GI metabolism of ethanol is quantitatively much lower. Various enzyme systems have been characterized in GI mucosal cells including various isozymes of alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP 2E1) and catalase. Gastric ADH activity is one factor by which first pass metabolism (FPM) is influenced and its activity is modulated by genetics, gender, age, drugs and gastric morphology. Another important factor in FPM of ethanol is the speed of gastric emptying. In addition to mucosal ethanol metabolism, ethanol can also be oxidized by many bacterial species in the upper GI tract including oropharynx and stomach as well as in the large intestine. GI metabolism of ethanol may influence systemic bioavailability of ethanol and may lead to local toxicity most likely mediated by acetaldehyde. Such toxicity could be of importance in ethanol-associated carcinogenesis.
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PMID:The role of gastrointestinal factors in alcohol metabolism. 937 95

GM0637, a human fibroblast cell line, was transfected with pCMV2E1, an expression vector containing the full length cDNA for rat cytochrome P450 2E1 (P450 2E1), and with pCMVneo, which contained vector alone, and the selected clones were designated GM2E1 and GMneo, respectively. Western blot analysis showed that GM2E1, but not GMneo, expressed a protein that reacted with anti-human P450 2E1 antibody. The 7-ethoxycoumarin O-deethylase,p-nitrophenol hydroxylase, and N-nitrosodimethylamine (NDMA) demethylase activities of the P450 in these cells were measured in monolayer cell cultures without preparing microsomes. Exposure of the GM2E1 cells to NDMA for 4 days caused severe decreases in cell viability, as determined by crystal violet uptake, and showed a sigmoidal dose-response curve with a median lethal dose of 17 microM. In contrast, the viability of GMneo cells was not altered by NDMA even at concentrations up to 10 mM. Time- and concentration-dependent methylation of DNA, RNA and protein by [14C]NDMA was only observed in cells expressing P450 2E1. Inhibitors of P450 2E1 activity such as ethanol, 4-methylpyrazole, and isoniazid caused a 90% decrease in the methylation of cellular macromolecules and also completely protected the cells against NDMA-mediated toxicity. The cytotoxicity due to exposure to NDMA was partially inhibited by antioxidants such as N-acetylcysteine, ascorbic acid, butylated hydroxyanisole and N-t-butyl-alpha-phenylnitrone but was not potentiated upon glutathione depletion. These results document the ability of rat P450 2E1 to metabolize NDMA to toxic reactive intermediates and demonstrate that this cell line provides a useful model for studying the mechanisms of metabolism-mediated toxicity and carcinogenesis.
Carcinogenesis 1998 Feb
PMID:Heterologous expression of rat P450 2E1 in a mammalian cell line: in situ metabolism and cytotoxicity of N-nitrosodimethylamine. 949 84


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