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

The role of metabolism of tumour promoters on the inhibition of intercellular communication was investigated in a modified V79 metabolic cooperation system. V79 cells, which stably express different rat cytochrome P450 enzymes (CYP1A1, CYP1A2 or CYP2B1), were used in the metabolic cooperation assay. The inhibitory effect on intercellular communication of four compounds was changed in cells expressing cytochrome P450 enzymes, compared to cells without. The phorbol ester TPA and di(2-ethylhexyl)phthalate blocked intercellular communication in all the cell lines tested, but expression of CYP1A1 enzyme reduced the inhibitory activity in these cells. Diethylstilbestrol caused inhibition only with cells containing cytochrome P450 enzymes. In contrast, the benzene metabolite hydroquinone inhibited metabolic cooperation preferentially in cells without cytochrome P450 enzymes. The inhibition of metabolic cooperation by another benzene metabolite, phenol, was not affected by the cytochrome P450 enzymes. The inhibitory activity of several chemicals that have not been tested previously was analysed in the new metabolic cooperation assay. The inhibitory activity of none of these chemicals was affected by cytochrome P450-associated metabolism. 7-Octylindolactam V was as potent as TPA, whereas the related indolactam V was 100-fold less active. The carcinogenic aromatic amine 4-aminobiphenyl, but not its primary metabolite 4-hydroxyaminobiphenyl, inhibited metabolic cooperation. Other known carcinogens, ochratoxin A, aflatoxin B1 and 4-nitrobiphenyl, did not inhibit metabolic cooperation in either V79 cells expressing or cells not expressing cytochrome P450. We conclude that cytochrome P450-associated metabolism plays an important role in the inhibition of gap junctional intercellular communication of some tumour promoters. The modified metabolic cooperation assay presented here is valuable for detecting some inhibitory chemicals which have been 'false negative' in previous assays for gap junctional intercellular communication. The assay also discloses that cytochrome P450 metabolism alters intercellular communication by a mechanism other than metabolism of the exogenous inhibitor.
Carcinogenesis 1993 Nov
PMID:Cytochrome P450-mediated metabolism of tumour promoters modifies the inhibition of intercellular communication: a modified assay for tumour promotion. 824 68

Osteogenic Disorder Shionogi (ODS) rats, which cannot synthesize ascorbic acid due to a deficiency of L-gulonolactone oxidase, become scorbutic when not supplied with dietary ascorbic acid. We used the deficient rats to study the effects of ascorbic acid on the amount of cytochrome P450 enzymes in liver microsomes. The total amount of hepatic cytochrome P450 in ODS rats deprived of ascorbic acid was lower by approximately 40%, whereas ODS rats fed with ascorbic acid and the wild strain had the same level of total hepatic cytochrome P450. Western blot analysis for various forms of cytochrome P450 in liver microsomes indicated that the amount of CYP1A2 was significantly higher in ascorbic acid deficient rats. On the other hand, amounts of CYP2B2 and 3A were lower, and those of CYP2E1 and CYP2C6/11 were unaffected. In accordance with the higher amount of CYP1A2, Northern blot analysis showed increased expression of CYP1A2 mRNA. The capacity of microsomes to produce mutagens from 2-amino-6-methyl-dipyrido[1,2-a:3',2'-d]imidazole acetate (Glu-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole acetate (Trp-P-2) was higher in scorbutic ODS rats by the Ames test. These results indicate that the effects of ascorbic acid deficiency on the expression of cytochrome P450 in ODS rat livers are form-specific and that the increased CYP1A2 is associated with increased metabolic activation of promutagens in the scorbutic state.
Carcinogenesis 1993 Dec
PMID:Increased CYP1A2 content and capacity to activate Glu-P-1 and Trp-P-2 in liver microsomes of scorbutic ODS rats. 826 14

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

Mono-specific antibodies targeted to human CYP1A1 and CYP1A2 have been produced by immunizing rabbits with protein conjugates of short synthetic peptides corresponding to residues 290-297 and 284-296 respectively, of these enzymes. The antibody targeted to CYP1A1 bound in immunoblotting to the recombinant protein expressed in yeast but did not bind to any human hepatic microsomal protein, whereas the antibody targeted to CYP1A2 bound only to this enzyme in immunoblotting of human hepatic microsomal fractions and did not recognize recombinant human CYP1A1. The intensity of hepatic microsomal CYP1A2 immunoreactivity (n = 5) correlated significantly with a number of activities characteristic of this enzyme: phenacetin O-deethylase (POD), ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-demethylase activities and the ability to activate the dietary carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), to a mutagen. The anti-CYP1A2 anti-peptide antibody consistently inhibited both POD and EROD activities, but inhibition was incomplete (28%). In view of the known (> 90%) contribution of CYP1A2 to these activities and the correlation with antibody binding, this is consonant with an epitope for the anti-CYP1A2 anti-peptide antibody that forms the edge of a functionally important proinhibitory surface region previously identified in rat cytochromes CYP1A. CYP1A2 immunoreactivity determined by immunoblotting correlated significantly with the ability of human hepatic microsomal fractions to activate 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP), another dietary carcinogen, to a mutagen. It is concluded that CYP1A1 is absent from human liver and that CYP1A2 is likely to be a major catalyst in the hepatic activation of PhIP.
Carcinogenesis 1993 Apr
PMID:Human hepatic CYP1A1 and CYP1A2 content, determined with specific anti-peptide antibodies, correlates with the mutagenic activation of PhIP. 847 19

Chemical carcinogenesis involves metabolism in the body of the carcinogen to the ultimate carcinogen and its interaction with DNA. There is considerable interindividual variation in the metabolic ability to activate as well as detoxify the carcinogens and in the ability to repair the carcinogen-DNA adducts. In many cases such differences occur as genetic polymorphisms and form the basis for variation in susceptibility to carcinogens and thereby to cancer risk. The activation mechanism is particularly related to the cytochromes P-450 (CYPs), and four of these are known to activate carcinogens: CYP1A1, CYP1A2, CYP2E1, and CYP3A4. Increased cancer risk has been related to polymorphisms in the CYPs and other activating enzymes. The DNA repair mechanisms show considerable complexity, and deficient repair mechanisms in certain human disorders are clearly related to increased cancer risk. Yet, there is no unambiguous epidemiological evidence available for cancer risk among individuals in general. In vivo methods have to be refined and developed for use in epidemiological studies.
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PMID:Cancer risk related to genetic polymorphisms in carcinogen metabolism and DNA repair. 847 97

Dietary indole-3-carbinol inhibits carcinogenesis in rodents and trout. Several mechanisms of inhibition may exist. We reported previously that 3,3'-diindolylmethane, an in vivo derivative of indole-3-carbinol, is a potent noncompetitive inhibitor of trout cytochrome P450 (CYP) 1A-dependent ethoxyresorufin O-deethylase with Ki values in the low micromolar range. We now report a similar potent inhibition by 3,3'-diindolylmethane of rat and human CYP1A1, human CYP1A2, and rat CYP2B1 using various CYP-specific or preferential activity assays. 3,3'-Diindolylmethane also inhibited in vitro CYP-mediated metabolism of the ubiquitous food contaminant and potent hepatocarcinogen, aflatoxin B1. There was no inhibition of cytochrome c reductase. In addition, we found 3,3'-diindolylmethane to be a substrate for rat hepatic microsomal monooxygenase(s) and tentatively identified a monohydroxylated metabolite. These observations indicate that 3,3'-diindolylmethane can inhibit the catalytic activities of a range of CYP isoforms from lower and higher vertebrates in vitro. This broadly based inhibition of CYP-mediated activation of procarcinogens may be an indole-3-carbinol anticarcinogenic mechanism applicable to all species, including humans.
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PMID:The anticarcinogen 3,3'-diindolylmethane is an inhibitor of cytochrome P-450. 856 33

The mutagenic 'fingerprint' of the cooked food carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was determined in a Chinese hamster cell line genetically engineered to express human CYP1A2 (XEMh1A2-MZ). The parental Chinese hamster V79 and XEMh1A2-MZ cells were exposed to PhIP at various concentrations for 24h. There was a dose-dependent increase in frequency of mutations at the hypoxanthine-guanine phosphoribosyltransferase (hprt) locus only in the metabolically competent XEMh1A2-MZ cells. The mutant frequency ranged from 25 to 90 X 10(-6) with final concentrations of 2.5 to 100 microM PhIP compared to 8 X 10(-6) in the solvent controls and the V79MZ cells. The molecular nature of the PhIP-induced mutations in XEMh1A2-MZ cells was determined by examining DNA sequence modifications at the hprt locus in forty five 6-thioguanine resistant (6-TGr) mutant clones. Single base substitutions predominantly GC-->TA transversions, were the major class of PhIP-induced mutation. However, a -1 frameshift 'hotspot' in a 5'-GGGA sequence was also observed. With the exception of a compound modification, all of the PhIP-induced mutations involved G.C base pairs. This is consistent with the previously observed PhIP-induced mutations in cultured mammalian cells and 32P-postlabelling experiments that show PhIP adducts to the guanine base and that major adduct is at the C8 position. Furthermore, nearly all of these mutations involved guanine bases on the non-transcribed strand which is possibly indicative of preferential repair of PhIP adducts from the transcribed strand. Nearest neighbor analysis of induced base substitutions indicates a preference for 5' guanine and 3' adenine. These data effectively define a mutation 'fingerprint' for PhIP, which may provide the basis for definitive studies on the role of PhIP in diet associated cancers such as tumours of colon. It is, therefore, intriguing that in their recent report of mutation in tumours of the colon induced by PhIP in male rate Kakiuchi et al. (Proc. Natl Acad. Sci. USA, 92, 910-914) report that four out of eight tumors had identical mutation of the tumour suppressor gene apc which is comprised of a -1 G frameshift in a 5'-GGGA sequence.
Carcinogenesis 1996 Apr
PMID:Mutational spectra of the dietary carcinogen 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine(PhIP) at the Chinese hamsters hprt locus. 862 68

Ingestion of cruciferous vegetables may prevent chemically induced carcinogenesis by their influence on specific cytochrome P450 enzymes (CYP) and phase II drug metabolizing enzymes in humans and rodents. Thus CYP enzymes are involved in transformation of procarcinogens, mutagens, steroid hormones and a large variety of other endogenous and exogenous components. In order to learn more about the influence of cruciferous vegetables on drug metabolizing enzymes in man two CYP enzymes previously suggested to be induced by vegetables were selected in an in vivo experiment in humans. Sixteen healthy non-smoking subjects, two females and 14 males, were exposed to three different types of diets and afterwards assayed for CYP1A2 catalysed caffeine metabolites and for CYP2E1 catalysed 6-hydroxylation of chlorzoxazone. Further, 2-hydroxyoestrone:16 alpha-hydroxylation ratios were determined in urine by means of a monoclonal antibody-based enzyme immunoassay. The three dietary periods were: (A) a customary home diet; (B) a 6 day standard diet avoiding well-known dietary inducers and inhibitors of CYP; (C) a 12 day dietary supplement to the standard diet of 500 g/day broccoli. The average 6-hydroxychlorzoxazone:chlorzoxazone ratio decreased by 21% (P < 0.05) after diet B compared with diet A in a 2 h plasma sample after ingestion of 500 mg chlorzoxazone. The ratio increased by 19% after diet C, however, this was not statistically significant. The caffeine metabolic ratio (CMR) was determined in urine 6 h after ingestion of 100 mg caffeine. The mean CMR increased by 5.5% when changing from diet A to diet B. When shifting to diet C the mean CMR increased a further 19% (P < 0.0005). The average 2-hydroxyoestrone:16 alpha-hydroxyoestrone ratio decreased by 1.3% when comparing diet A with diet B. Daily broccoli intake increased the ratio by 29.5% (P < 0.05). A low correlation of CMR with the 2-hydroxyoestrone:16 alpha-hydroxyoestrone ratio indicates that human CYP1A2 and other CYP enzymes involved in oestrone 2-hydroxylation are induced by dietary broccoli. On the other hand, the catalytic activity of CYP2E1 is not affected to the same degree by dietary broccoli.
Carcinogenesis 1996 Apr
PMID:Effects of dietary broccoli on human in vivo drug metabolizing enzymes: evaluation of caffeine, oestrone and chlorzoxazone metabolism. 923 Feb 94

MeIQx, a potent bacterial mutagen formed when meat is cooked, requires metabolic activation to exert its genotoxicity, a reaction catalysed primarily by CYP1A2 in adult mammals. Little is known about mammalian developmental changes in the mutagneic activation of compounds such as MeIQx. In rabbits we have shown previously that expression of CYP1A2 increases with age and is inducible by 3-methylcholanthrene (MC) from as early as 4 days pre-parturition. We have therefore investigated the effect of age on rabbit liver activation of MeIQx (assessed in an Ames test using Salmonella typhimurium TA98) before and after treatment of the animals with MC. MeIQx activation could not be detected using hepatic microsomal fractions from rabbits of <17 days of age. Thereafter activation increased with age to peak in weanling animals. Following MC treatment MeIQx activation was increased, being detectable in samples from rabbits as young as 9-11 days. The inducibility of MeIQx activation increased with age, reaching a plateau between 17 and 35 days. These rates of activation were broadly parallel to the changes in CYP1A2 specific content. These results indicate that the ability of rabbit liver to activate MeIQx is dependent on CYP1A2 activity, the expression of which is developmentally regulated. Although it has been established that human activation of MeIQx is also CYP1A2 dependent, whether a similar situation exists in infant humans has yet to be determined, although there is evidence that CYP1A2-dependent activity reaches a peak in late childhood.
Carcinogenesis 1996 Mar
PMID:Developmental changes in hepatic activation of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline in rabbit. 863 Nov 44

Expression of P-glycoprotein (P-gp), the mdr gene product, was investigated in primary cultures of rat and human hepatocytes exposed to 2-acetylaminofluorene (2-AAF). Increased levels of mdr1 mRNAs were evident in 2-AAF-treated rat hepatocytes by Northern blot analysis using rat mdr gene-specific probes, while transcripts of the mdr2 and mdr3 genes were decreased and unaffected respectively. Rat hepatocytes exposed to 2-AAF were also found to accumulate doxorubicin, an anticancer drug known to be transported by P-gp, poorly, thereby demonstrating that 2-AAF-mediated mdr1 induction resulted in increased P-gp activity. In contrast to their rat counterparts, human hepatocytes obtained from 10 individuals exhibited no change in both MDR1 and MDR2 mRNA levels, as well as in doxorubicin intracellular retention, in response to 2-AAF treatment, while cytochromes P-450 CYP1A1 and CYP1A2 were induced in both human and rat hepatocyte cultures. These data provide strong evidence that regulation of expression of mdr genes in liver cells in response to carcinogens such as 2-AAF is gene- and species-specific.
Carcinogenesis 1996 May
PMID:Differential regulation of mdr genes in response to 2-acetylaminofluorene treatment in cultured rat and human hepatocytes. 864 Sep 28


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