Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Epidemiological evidence suggests that the presence of human papillomaviruses (HPV), when combined with smoking behaviors, considerably enhances the risk of developing oral, cervical, vulvar, and/or anal carcinomas. It is well established that the cytochrome P450 (CYP), microsomal epoxide hydrolase (mEH), and other biotransformation enzymes are important modulators of the bioactivation and detoxification of many environmental chemicals, including constituents of tobacco smoke such as certain nitrosamines and polycyclic aromatic hydrocarbons (PAH). Since there is little information regarding oral and cervical epithelial-specific expression of these genes, established primary and HPV-immortalized oral and cervical epithelial cell lines were analyzed for morphology, mRNA and protein expression patterns of specific CYPs and mEH. Primary human oral and cervical epithelial cells were immortalized using retroviral infection with HPV-16 E6/E7 genes. Primary human keratinocyte cells were immortalized by transfection of HPV-18 and made tumorigenic with nitrosomethylurea treatment. Expression profiles for mEH, CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP3A, and CYP2E1 were evaluated in these cultures in the presence or absence of a PAH inducer, using reverse transcriptase-coupled polymerase chain reaction analysis. mEH gene expression was evident in all cultures, while CYP2A6 mRNA was not detected in any of the cell lines, regardless of culture conditions. CYP2E1 mRNA expression was greatest in the oral epithelial cultures and detectable in all other epithelial cultures except for the HPV-18 immortalized keratinocyte cell line. Elevated levels of CYP2D6 mRNA existed in both oral epithelial cell lines and the HPV-16 immortalized cervical epithelial cells when compared to the other cell lines examined. CYP1A1 and CYP1A2 mRNAs were detected in all the cells and several cultures were inducible by PAH exposure. To corroborate the RT/PCR data, Western immunoblotting experiments were conducted on selected samples. Using these methods, CYP1A1 and CYP2E1 proteins were detected in primary and HPV-immortalized oral and cervical epithelial cultures. These data indicate that both primary and HPV immortalized cells appear to express certain biotransformation enzymes necessary for the activation of tobacco-specific nitrosamines and PAHs. Although the overall impact of HPV gene infection on expression of these systems remains to be fully elucidated, as in vitro system is characterized which should prove useful in examining interactive mechanisms of HPV with xenobiotic activation in the etiology of squamous cell carcinomas.
Carcinogenesis 1995 Jun
PMID:Expression of cytochrome P450 and microsomal epoxide hydrolase in cervical and oral epithelial cells immortalized by human papillomavirus type 16 E6/E7 genes. 761 6

Male Fischer rats were maintained for a period of 17 weeks on an iron-deficient diet along with suitable controls. The effect of long term deprivation of iron on xenobiotic metabolism was studied by the activities of various drug metabolising enzymes in both liver as well as extra-hepatic tissues like lungs, kidneys and intestinal mucosa (I.M.). The results show that among the Phase I (activating) enzymes, the hepatic activities of benzo(a)pyrene hydroxylase (AHH) and microsomal epoxide hydrolase (mEH) are significantly reduced in iron deficiency. The other parameters of the activating system, namely cytochrome P450, aminopyrene demethylase (ADM) and aniline hydroxylase (AH), are not altered. Of the two Phase II (conjugating) enzymes studied, only uridine diphospho glucuronyl transferase (UDPGT) is found to be depressed, but not glutathione S-transferase (GST) in liver in iron deficiency. Activities of Phase I enzymes are markedly lowered in extra-hepatic tissues compared to liver; such depression is not observed in conjugating enzymes. Iron deficiency does not seem to make much impact on the enzyme activities of extra-hepatic tissues. Overall, the hepatic results suggest a defect in detoxification mechanisms in iron deficiency. Such impairment may very well predispose an iron-deficient host to an increased risk of carcinogenesis.
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PMID:Effect of long term iron deficiency on the activities of hepatic and extra-hepatic drug metabolising enzymes in Fischer rats. 785 40

N-acetyltransferases have an important role in the metabolism of arylamine and hydrazine drugs and carcinogens. Human N-acetylation phenotype may predispose individuals toward a variety of drug and xenobiotic-induced toxicities and carcinogenesis. Syrian hamsters express two N-acetyltransferase isozymes; one varies with acetylator genotype (polymorphic) and has been termed NAT2; the other does not (monomorphic) and has been termed NAT1. The intronless NAT1 coding region was cloned via the polymerase chain reaction from homozygous rapid acetylator and homozygous slow acetylator congenic and inbred hamster genomic DNA templates and sequenced. The NAT1 alleles from the homozygous rapid (NAT1) and homozygous slow (NAT1s) acetylator hamsters differed in one nucleotide, but the mutation is silent with no change in deduced amino acid sequence. To characterize the enzyme products of the NAT1 alleles, we developed a prokaryotic-expression system. The NAT1r and NAT1s alleles were amplified by expression-cassette polymerase chain reaction and subcloned into the tac promoter-based plasmid vector pKK223-3 for over-production of recombinant NAT1 in E. coli strain JM105. Induced cultures from selected NAT1-inserted transformants yielded high levels of soluble protein capable of N-acetylation, O-acetylation, and N,O-acetylation. The recombinant NAT1r and NAT1s proteins did not differ in substrate specificity, specific activity, Michaelis-Menten kinetic properties, intrinsic stability, and electrophoretic mobility. Also, the over-expressed NAT1 proteins displayed substrate-specificity and electrophoretic mobilities characteristic of NAT1 isolated from Syrian hamster liver and colon cytosols.
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PMID:Syrian hamster monomorphic N-acetyltransferase (NAT1) alleles: amplification, cloning, sequencing, and expression in E. coli. 808 15

The hydroxysteroid sulfotransferases (HSTs) are phase II drug metabolizing enzymes which play a role in xenobiotic detoxication, carcinogen activation, and intratissue hormone modulation. Rat liver contains three principal HST enzymes. Of these, HST-a is most abundant in female rat liver. The phase I drug metabolizing enzyme cytochrome P450 1A1 (CYP1A1) provides a major pathway for polycyclic aromatic hydrocarbon (PAH) carcinogen activation, whereas HST-a, through enzymatic sulfation, offers an alternative pathway for PAH carcinogen activation. Transcription of the rat hepatic CYP1A1 gene is induced in response to treatment with PAH carcinogen 3-methylcholanthrene (3-MC). In view of the potential importance of enzymatic sulfation to the complex process of PAH carcinogenesis, the effect of 3-MC on HST-a gene expression was investigated. Groups of prepubescent (aged approximately 22-30 days) and young adult female (aged approximately 69-84 days) Sprague-Dawley rats were injected ip with corn oil vehicle or with 3-MC (80 mg/kg). After fasting for 24 hr, rats were terminated and hepatic HST-a gene expression was analyzed using slot blot, Northern blot, and Western blot analyses. Initial Northern blot and slot blot analyses demonstrated a substantial suppression of rat hepatic HST-a mRNA in both prepubescent and young adult female rats. Subsequent Northern blot analyses on liver tissue isolated from female rats aged approximately 55 days confirmed CYP1A1 mRNA induction in 3-MC-treated animals and demonstrated a dose-dependent suppression of HST-a mRNA expression of approximately 25, 50, and 75% in rats treated with 10, 25, and 80 mg/kg 3-MC ip, respectively. In contrast, HST-a protein levels remained unaltered 24 hr after 3-MC treatment. A time-course study revealed that hepatic HST-a mRNA levels returned to control levels by 36 hr following 3-MC treatment. These results suggest that xenobiotics such as 3-MC modulate HST-a mRNA expression and that HST-a mRNA suppression after 3-MC treatment may occur at the level of transcription.
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PMID:Suppression of hydroxysteroid sulfotransferase-a gene expression by 3-methylcholanthrene. 812 88

Several chemicals have been shown, within the limits of epidemiology, to be thus far not carcinogenic in humans at systemic exposure levels similar to those associated with carcinogenicity in rodents. The data are discussed in terms of mechanisms which appear to operate in rodents but not in humans. Pharmacokinetic methods for interspecies comparisons must always be validated by a complementary scrutiny of the pharmacodynamic processes involved, i.e., by considering the responsiveness of the species in question to a given systemic concentration of xenobiotic. For carcinogenesis this validation step is usually beyond reach, due to the time frame for the onset of cancer in humans. For these reasons it is argued that, in the absence of knowledge of mechanisms, there is usually no scientific basis for using the concentrations of a xenobiotic that occur in body fluids or tissues during a rodent carcinogenicity test to make a quantitative carcinogenic risk assessment in humans.
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PMID:The paradoxical lack of interspecies correlation between plasma concentrations and chemical carcinogenicity. 809 Sep 56

Chemically-induced mutagenesis and carcinogenesis is modulated by various plant products, some of which are present in the human diet. 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent carcinogen in tobacco and tobacco smoke, is activated by microsomal enzymes. In this study, we investigated the effects of capsaicin on the in vitro metabolism of NNK. Capsaicin is the principal component of Capsicum fruits used widely by humans as a food additive. Liver microsomes from saline-injected, phenobarbital-induced and beta-naphthoflavone-induced hamsters were used. Microsomes from phenobarbital and beta-naphthoflavone-induced animals expressed decreased NNK reduction and enhanced pyridine-N-oxidation, but did not significantly alter alpha-carbon hydroxylation of NNK. Capsaicin (0.5 mM) inhibited the formation of all metabolites of NNK by all microsomal fractions and inhibited alpha-hydroxylation by phenobarbital-induced microsomes more than by either of the other two treatments. Our results suggest that capsaicin, as a naturally occurring dietary constituent, possesses antimutagenic and anticarcinogenic properties through the inhibition of xenobiotic metabolizing enzymes.
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PMID:Effects of capsaicin on liver microsomal metabolism of the tobacco-specific nitrosamine NNK. 828 80

The consequences of altered cytochrome P450-dependent monooxygenase activities in colonic tissue are unknown. As an initial step toward elucidating underlying mechanisms that regulate cytochrome P450 levels in colonic epithelium, we have characterized CYP1A1(3) induction in cultured human colonic cells (Caco-2). The induction of CYP1A1 by several inducers was measured by enzymatic activity and immunoreactivity. 3-Methylcholanthrene, beta-naphthoflavone, and benz[alpha]anthracene were strong inducers of CYP1A1, benzo[alpha]pyrene induced CYP1A1 activity only weakly, while benzo[e]pyrene and phenobarbital were essentially inactive as inducers. The response of Caco-2 cells to beta-naphthoflavone is similar to that previously observed in vivo in the rat colonic epithelium. In addition, we have demonstrated that this induction results from an increase in CYP1A1 transcriptional activity. These results suggest that the Caco-2 cell line exhibits certain characteristics of cytochrome P450 activity observed in colonic epithelium and may serve as a model for studying cytochrome P450-dependent activity in this tissue. The identification of a colonic cell line that responds to xenobiotic inducers will be useful for examining mechanisms of cytochrome P450 induction in the colon and elucidating the potential role of this system in colonic carcinogenesis.
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PMID:Regulation of cytochrome P450 in cultured human colonic cells. 838 Sep 63

The effects of sodium butyrate, which has been shown to act as a differentiation promoting agent in several different tumor cell lines, were studied in a rat liver nonparenchymal epithelial cell line. Exposure of these cells to 3.75 mM butyrate resulted in an inhibition of cell proliferation and, at the same time, an increase in cell diameter (2- to 6-fold) and size of the nuclei (approximately 2-fold) after 3 days in culture. Binucleated cells arose, comprising approximately 12% of the cells investigated, and the number of cells with an abnormal set of chromosomes was increased. Intercellular communication, measured by dye transfer of Lucifer Yellow, was unchanged. From the various xenobiotic metabolizing enzyme activities measured, only those of glutathione S-transferases were significantly altered (increases of 4- to 9-fold) by butyrate treatment. These increases were mainly due to the predominant rise in the pi class isoenzyme which is a well-known tumour marker in rat hepatocarcinogenesis. Thus, our results cannot be interpreted as being either due to promotion of differentiation or due to transformation. The state and type of cell under study has to be considered and investigations of further differentiation parameters are needed to obtain a deeper insight into the biological activity and the underlying mechanisms of cell state modifying agents like butyrate.
Carcinogenesis 1993 Mar
PMID:Effects of sodium butyrate on DNA content, glutathione S-transferase activities, cell morphology and growth characteristics of rat liver nonparenchymal epithelial cells in vitro. 845 22

1-Hydroxymethylpyrene (HMP), a primary benzylic alcohol, and 4H-cyclopenta[def]chrysen-4-ol (OH-CPC), a secondary benzylic alcohol, were investigated for mutagenicity in Salmonella typhimurium (reversion of the his- strain TA98) in the presence of various xenobiotic-metabolizing systems. In the direct test, HMP was inactive and OH-CPC was very weakly active. In the presence of NADPH-fortified postmitochondrial fraction from rat liver (S9/NADPH), no activation of OH-CPC was observed, whereas strong mutagenic effects were elicited by HMP. In the presence of cytosol and 3'-phosphoadenosine-5'-phosphosulfate (PAPS), both alcohols were activated to potent mutagens. For equal mutagenic effects, approximately 650-fold lower concentrations of HMP were required in the cytosol/PAPS-mediated assay than in the S9/NADPH-mediated assay. The cytosol/PAPS-mediated mutagenicity of both alcohols was 3- to 4-fold enhanced, when KCl (125 mM) was present during the exposure. The authentic chloromethylarenes, 1-chloromethylpyrene and 4-chloro-4H-cyclopenta[def]chrysene, showed very strong direct mutagenicity. These results, taken together with previous findings, indicate that both primary and secondary benzylic alcohols derived from polycyclic aromatic hydrocarbons may be activated by sulfotransferases to electrophilic sulfuric acid esters, and by subsequent substitution reaction to further active species such as benzylic chlorides.
Carcinogenesis 1993 Apr
PMID:Sulfotransferase-mediated mutagenicity of 1-hydroxymethylpyrene and 4H-cyclopenta[def]chrysen-4-ol and its enhancement by chloride anions. 847 21

Many arylalkyl isothiocyanates are potent inhibitors of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in rats and mice. In the mouse, 4-phenylbutyl isothiocyanate (PBITC) and 6-phenylhexyl isothiocyanate (PHITC) exhibited greater inhibition than benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC). The present study was conducted to investigate the structure-activity relationships of these four arylalkyl isothiocyanates for their inhibition of NNK oxidation and effects on xenobiotic-metabolizing enzymes in rats and mice. A single dose (0.25 or 1.00 mmol/kg) of each isothiocyanate was given to F344 rats 6 or 24 h before death. The rates of NNK oxidation were decreased in microsomes from the liver, lung and nasal mucosa of rats. Generally, PEITC was more potent than BITC but less potent than PBITC and PHITC. The rates in rat liver microsomes were decreased at 6 h but recovered or increased at 24 h; the rates in rat lung microsomes were markedly decreased at both 6 and 24 h; and the rates in rat nasal mucosa microsomes were also significantly decreased. The same treatment decreased the rat liver N-nitrosodimethylamine demethylase activity dramatically and ethoxyresorufin O-dealkylase and erythromycin N-demethylase activities moderately. However, the rat liver microsomal pentoxy-resorufin O-dealkylase activity was decreased at 6 h but increased at 24 h, with PEITC showing the most marked induction. The rat liver NAD(P)H:quinone oxidoreductase activity was increased 1.4- to 3.3-fold, with PEITC being most effective; and the glutathione S-transferase activity was increased slightly. Similarly, at a single dose of 0.25 mmol/kg (5 mumol/mouse) 24 h before death, PEITC, PBITC, PHITC but not BITC, decreased NNK oxidation in mouse lung microsomes by 40-85%, with PBITC and PHITC showing greater inhibition. Furthermore, all four isothiocyanates extensively inhibited NNK oxidation in rat lung and nasal mucosa microsomes as well as mouse lung microsomes in vitro, with PEITC (IC50 of 120-300 nM) being more potent than BITC (IC50 of 500-1400 nM) but less potent than PBITC and PHITC (IC50 of 15-180 nM). PHITC was a very potent competitive inhibitor of NNK oxidation in mouse lung microsomes with apparent K(i) values of 11-16 nM. These results indicate that PBITC and PHITC are more potent inhibitors of NNK bioactivation in rats and mice than PEITC. In addition, these arylalkyl isothiocyanates could be effective in protecting against the actions of a broad spectrum of carcinogenic or toxic compounds.
Carcinogenesis 1993 Jun
PMID:Structure-activity relationships of arylalkyl isothiocyanates for the inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone metabolism and the modulation of xenobiotic-metabolizing enzymes in rats and mice. 850 4


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