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 effect of various co- and anti-carcinogens of colon carcinogenesis on the metabolism of benzo(a)pyrene (BP) in cultured rat colon is reported. Rat colon enzymatically converted BP into metabolites which bind to cellular macromolecules i.e., DNA and protein. Activity of aryl hydrocarbon hydroxylase (AHH) activity and binding levels of BP to macromolecules were higher in the descending colon when compared to other segments. The major metabolites of BP, extractable with ethylacetate, were quinones, tetrols, 7,8-diol and a peak containing 9,10-dihydroxy-9,10-dihydrobenzo(a)pyrene and 7,8,9-trihydroxy-7,8-dihydrobenzo(a)pyrene. The binding levels of BP to DNA and protein in the explant was lowered by co-incubation with 7,8-benzoflavone (7,8-BF) (3.6 and 18.0 micron), a known inhibitor of AHH, and with disulfiram (100 micron), an anti-oxidant. The absence of vitamin A in the media also resulted in a lower level of BP binding to DNA and protein and in lower activity of AHH. Pretreatment with known inducers of AHH such as phenobarbital (PB) or benz(a)anthracene (BA), did not have any significant effect on the binding levels of BP to DNA or on the AHH activity. Of the bile acids investigated only taurodeoxycholic acid significantly increased the binding level of BP to DNA.
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PMID:Effect of various chemicals on the metabolism of benzo(a)pyrene by cultured rat colon. 91 16

The potent hepatocarcinogen 3-methoxy-4-aminoazobenzene (3-MeO-AAB) has been reported to be bioactivated to mutagenic intermediates by rat liver microsomal cytochrome P450 (P450) and to be a selective inducer of rat P450IA2. In this study we have further investigated the roles of individual rat and human P450 enzymes in the bioactivation of this hepatocarcinogen in a Salmonella typhimurium TA1535/pSK1002 system where umu response is indicative of DNA damage. 3-MeO-AAB was found to be bioactivated by liver microsomal enzymes from rats and humans in this assay system. The liver microsomal activities are increased by pretreatment of rats with various P450 inducers such as phenobarbital (PB), beta-naphthoflavone (BNF), dexamethasone (DEX), acetone, ethanol, isoniazid (INH), diphenylhydantoin and valproic acid, and can be inhibited considerably by SKF-525A and metyrapone. alpha-Naphthoflavone (ANF) is also an inhibitor for the reaction catalyzed in BNF-treated rats, but stimulated the microsomal activity in DEX-treated rats. Evidence has also been obtained that specific antibodies raised against P450IIB1, P450IA1 or IA2, P450IIE1, and P450IIIA2 inhibited the activation in liver microsomes from rats pretreated with PB, BNF, INH and DEX respectively, suggesting the possible roles of several P450 enzymes in the bioactivation of 3-MeO-AAB. The results obtained with reconstituted monooxygenase systems containing various rat P450 enzymes are highly supportive of this conclusion. Human liver microsomal activation of 3-MeO-AAB was also inhibited to various extents by antibodies raised against P450IA2, P450MP, P450IIE1 and P450IIIA4. In a reconstituted system containing purified forms of human P450, P450IA2 was the most active in catalyzing 3-MeO-AAB, followed by P450IIIA4 and P450MP. ANF, a known activator of P450IIIA-catalyzed reactions, caused an increase in activation of 3-MeO-AAB in human liver microsomal and P450IIIA4- and P450MP-containing reconstituted systems. From these results it is concluded that multiple P450 enzymes in rat and human liver microsomes are involved in the bioactivation of 3-MeO-AAB, regardless of its selective induction of the rat P450IA2 gene.
Carcinogenesis 1991 Jan
PMID:Roles of different cytochrome P450 enzymes in bioactivation of the potent hepatocarcinogen 3-methoxy-4-aminoazobenzene by rat and human liver microsomes. 198 74

Diethylstilbestrol-4',4"-quinone (DES Q) has previously been postulated to be a reactive intermediate in diethylstilbestrol (DES) metabolism. DES is oxidized to DES Q in vitro, but the occurrence of the quinone metabolite in vivo has not yet been demonstrated due to its instability and chemical reactivity. In this report, the characteristics of in vitro formation of DES Q and the isolation of 3H-labeled DES Q from tissue extracts of hamsters injected with radiolabeled DES is described. In vitro, the time-dependent formation of DES Q as a function of microsomal protein, cofactor or substrate concentrations was demonstrated. The microsome-mediated oxidation of DES to quinone was inhibited by various compounds that also effectively inhibit the peroxidatic activity of cytochrome P-450. In vivo, the formation of DES Q occurred in all tissues investigated, livers and kidneys of male and female adult hamsters, neonates and fetuses, and in uterus and placenta. Concentrations of quinone metabolite in liver and kidney of adult hamsters after injection of 75 mumol/kg DES were 76 and 20 pmol/g tissue respectively. In neonates and fetus, concentrations of DES Q after the same dose of DES were markedly less than those in adults (0.026 and 0.047% of adult levels in neonatal liver and kidney and 0.013 and 0.016% of adult levels in fetal liver and kidney respectively). Since DES Q was also formed by fetal liver homogenate in vitro, fetal oxidizing enzymes appear to be the source of the quinone metabolite in this tissue. DES Q concentrations were also examined after injection of DES into hamsters pretreated with vitamin C or alpha-naphthoflavone, substances known to inhibit DES-induced renal carcinogenesis. Quinone metabolite levels were cut in half in response to vitamin C in correlation with the approximately 50% decrease in DES-induced renal tumors reported previously. alpha-Naphthoflavone pretreatment decreased renal and hepatic DES Q concentrations by 70 and 17% respectively, also in correlation with the known prevention of kidney tumors by this flavone. These data support a role of DES Q in DES-induced carcinogenesis. Since there is no correlation between DES Q concentrations and target site specificity of DES induced tumors, the oxidation of DES to DES Q and the genotoxicity of this metabolite may be a necessary but not sufficient event in tumor development. Hormone-dependent growth of initiated cells may also be necessary for the occurrence of cancers.
Carcinogenesis 1989 Jul
PMID:Metabolic oxidation of diethylstilbestrol to diethylstilbestrol-4',4"-quinone in Syrian hamsters. 273 17

7,8-Benzoflavone (BF) was applied orally via stomach tube in doses of 50, 100, 200 and 400 mg/kg body weight to pregnant NMRI mice on the 18th day of gestation. BF application was followed 1 h later by oral administration of 60 mg/kg body weight dimethylbenz[a]anthracene (DMBA). As a rule this dose of DMBA does not lead to prenatal secondary effects and is not carcinogenic to either the mother animals or the F1 generation. Subsequent promotion of the F1 generation with the tumour promoter 12-O-tetradecanoylphorbol-13-acetate over a period of 12 weeks resulted in a high yield of skin papillomas and lung adenomas when no BF had been applied. With prior application of BF, the tumour yield could be significantly reduced.
Carcinogenesis 1986 Jul
PMID:Inhibition of the prenatal dimethylbenz[a]anthracene-induced tumour initiation in mice by prior administration of 7,8-benzoflavone. 308 48

7,8-Benzoflavone (7,8-BF), over a dose range of 0.1-10 microM, partially inhibited the synthesis of prostaglandin E2 (PGE2) in primary cultures of epidermal cells from SENCAR mice, and completely suppressed the TPA-dependent stimulation of PGE2 synthesis. Under identical conditions 7,8-BF also partially suppressed ornithine decarboxylase (ODC) activity in both unstimulated and TPA stimulated cultures. The finding that 7,8-BF inhibition of TPA-induced ODC can not be overcome by addition of exogenous PGE2 suggests that ODC induction by TPA involves a prostaglandin-independent component.
Carcinogenesis 1986 Jun
PMID:7,8-Benzoflavone: an inhibitor of prostaglandin synthesis and ornithine decarboxylase in murine epidermal cultures. 345 47

Kinetic analysis of oxidative metabolism of 2-acetylaminofluorene (AAF) was studied in control and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced microsomes and with six highly purified cytochrome P-450 isoenzymes from rabbit liver. Kinetic parameters were defined for 7-, 5-, 3-, 1- and N-hydroxylations of AAF. 7-Hydroxylation was best defined by a two enzyme system, displaying a high affinity and relatively low capacity and a low affinity high capacity components in both control and TCDD induced microsomes. All the purified cytochrome P-450 isoenzymes were capable of catalyzing the 7-hydroxylation of AAF and, with the exception of form 4, this was the only oxidation on the AAF molecule catalyzed by these forms. It is probable that forms 1, 4 and 6 accounted for a substantial part (greater than or equal to 25%) of total metabolic capacity corresponding to the high affinity component of 7-hydroxylation, whereas forms 3b and 3c accounted for less than 5% of the metabolic capacity displayed by the low affinity component in control microsomes. However, forms 4 and 6 could account for greater than 90% of the metabolic capacity of the high affinity component of 7-hydroxylation in TCDD microsomes, whereas the form(s) responsible for the metabolic capacity of the low affinity component were not identified. Each of the 1-, 3-, 5- and N-hydroxylations were best defined by a single enzyme system in both control and TCDD microsomes (3- and 5-hydroxylations could not be defined in TCDD microsomes). Close agreements were found between the apparent Km for N-hydroxylation in control, TCDD induced microsomes and with form 4. alpha-Naphthoflavone inhibited AAF N-hydroxylation to a similar extent in control and TCDD microsomes and in form 4. These date indicate that: a subpopulation of cytochrome P-450 isoenzymes, which includes all the purified P-450 forms tested in the present study, is solely involved in detoxification (i.e., 7-hydroxylation) of AAF, and as such probably behave as a functional unit in vivo; modulation of cytochrome P-450 content by inducers such as TCDD results in emergence of relatively few cytochrome P-450 isoenzymes that can account for most of the oxidative metabolism of AAF; and a single cytochrome P-450 isoenzyme (i.e., form 4) is responsible for catalyzing N-hydroxylation of AAF, the first and the obligatory step in the metabolic activation of this carcinogen.
Carcinogenesis 1984 Dec
PMID:Metabolic processing of 2-acetylaminofluorene by microsomes and six highly purified cytochrome P-450 forms from rabbit liver. 649 23

The biology of tumor formation by the initiation-promotion protocol differs from that of the complete carcinogenesis process. In the latter case, the latency period is longer and tumor yield is less, but carcinomas appear much earlier. Retinoic acid, a potent inhibitor of both the induction of ODC activity and tumor promotion by TPA, failed to inhibit both the induction of ODC activity and tumor formation by DMBA. 7,8-Benzoflavone, which did not inhibit the induction of ODC activity by TPA, inhibited the induction of ODC activity and tumor formation by DMBA. The results indicate that: (a) mechanism of the induction of ODC activity and tumor formation by a complete carcinogen appears to be different from that of the tumor promoter TPA; (b) DMBA-induced ODC activity may be an important component of the mechanism of DMBA carcinogenesis; and (c) although there is a wealth of data that indicate the efficacy of the retinoids in the prevention of a variety of cancers in experimental animals, including mammary carcinogenesis by DMBA (3,5), the present results and those reported by others (2) are not in agreement with a universal effect of retinoic acid in the prevention of carcinogenesis.
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PMID:The differential effects of retinoic acid and 7,8-benzoflavone on the induction of mouse skin tumors by the initiation-promotion protocol and by the complete carcinogenesis process. 680 91

A murine keratinocyte cell-mediated mutagenesis assay was characterized and examined as an in vitro model system for studying the biotransformation of promutagens/procarcinogens by mouse skin. The assay used living cultured newborn SENCAR keratinocytes for the metabolic activation of promutagens and Chinese hamster lung V-79 fibroblasts for detection of resulting mutagens. Mutations at, or affecting, the hypoxanthine-guanine phosphoribosyltransferase locus were scored by resistance to 6-thioguanine. The relative mutagenicities of several polycyclic aromatic hydrocarbons (PAHs) in the cell-mediated assay correlated with the in vivo skin tumorigenicity of the PAHs determined in a two-stage carcinogenesis protocol. Metabolic activation of the promutagenic PAHs to ultimate mutagens was dependent upon the presence of the cultured keratinocyte feeder layer. 7,8-Benzoflavone, a potent inhibitor of 7,12-dimethylbenz[a]anthracene (DMBA)-dependent initiation in mouse skin, inhibited DMBA-dependent mutagenesis in the cell-mediated assay in a concentration responsive manner. The non-PAH promutagens, dimethylnitrosamine (DMN) and sterigmatocystin (STC) were both activated by cultured keratinocytes to cytotoxic derivatives. DMN was neither mutagenic in the cell-mediated assay nor tumorigenic in mouse skin when tested in a two-stage carcinogenesis protocol. STC was weakly mutagenic and tumorigenic in mouse skin.
Carcinogenesis 1983
PMID:Keratinocyte cell-mediated mutagenesis assay: correlation with in vivo tumor studies. 683 37

p53 inhibits cell cycle progression and DNA damaging cytostatics induce p53 protein expression, indicating that p53 responds to DNA damage. We have measured benzo[a]pyrene (BP)-induced DNA damage in association with p53 expression. The most relevant DNA adducts for carcinogenesis, benzo[a]pyrene-7,8-diol-9,10-epoxide-DNA adducts, were measured by synchronous fluorescence spectrophotometry and p53 immunohistochemistry using polyclonal antibody CM1, which detects both wild-type and mutated forms of p53. Activation of BP in A-549 lung carcinoma and MCF-7 breast adenocarcinoma cell lines containing wild-type p53 was followed by an increase in p53 protein expression. alpha-Naphthoflavone, an inhibitor of cytochrome P450 (CYP)1A1, decreased both the formation of diolepoxide metabolites and the p53 response. The cell lines not able to activate BP, A-427 and SK-LU-1 (both human lung carcinomas), SK-MES-1 (human lung squamous carcinoma) and human fibroblasts, did not show any increase in p53 immunohistochemistry. The OVCAR-3 ovarian adenocarcinoma cell line, containing a mutation in exon 7 of p53, and the SK-LU-1 cell line expressed very high levels of p53 protein before BP treatment and no increase in p53 immunohistochemistry was seen. These findings indicate that p53 protein is part of the response of the cells to BP-induced DNA damage.
Carcinogenesis 1995 Sep
PMID:p53 protein expression is correlated with benzo[a]pyrene-DNA adducts in carcinoma cell lines. 755 63

Bacterial assays were used to examine the activation of 14 known procarcinogens by cytochrome P450 (P450) enzymes. Human P450s 1A1, 1A2 and 3A4 were expressed in Escherichia coli with slight modification of their N-terminal sequences. Genotoxicity was measured by the induction of the SOS response in Salmonella typhimurium NM2009 (TA1535/pSK1002/pNM12), which contains a umuC regulatory sequence attached to the lacZ reporter gene. Conditions for analysis were examined using E. coli membranes and purified enzymes. Membrane fractions, fortified with NADPH-P450 reductase, were found to be useful preparations for measuring activation of the procarcinogens. Conditions of linearity were established for these assays and the systems were applied to several particular problems related to bioactivation of procarcinogens by P450s. The patterns of activation of the 14 individual chemicals were consistent with the literature developed using human liver microsomes, purified liver P450s and other approaches. The P450s expressed in bacterial membranes could be inhibited by antibodies. 7,8-Benzoflavone inhibited P450s 1A1 and 1A2 and stimulated P450 3A4 in the membranes. The contributions of P450s 1A1 and 1A2 were distinguished with some of the arylamines and 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene. Recombinant P450 3A4 was found to be more active than P450 1A2 in the activation of aflatoxin B1 at all substrate concentrations examined.
Carcinogenesis 1994 Nov
PMID:Activation of procarcinogens by human cytochrome P450 enzymes expressed in Escherichia coli. Simplified bacterial systems for genotoxicity assays. 795 1


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