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)

An improved high-pressure liquid chromatography system was used to analyze the amount of benzo[a]pyrene metabolites formed in reconstituted microsomal mixed-function oxidase systems containing different cytochromes P-450. We separated twelve identified and seven unknown metabolites of BP which included three diols: the 9,10-, 4,5-and 7,8-dihydrodiols; four phenols, 9-,7-, 1-, and 3-hydroxybenzo[a]pyrene (OH-BP); and three quinones: the 1,6-. 3,6-, and 6,12-quinones. Two additional peaks co-migrated with synthetic 4-OH-BP and 5-OH-BP, respectively. The former, designated fraction 1, was shown by u.v. spectra to contain primarily the 4,5-epoxide with small amounts of 4-OH-BP. The total metabolism of BP was found to be approximately 20-fold greater with the cytochrome P-450 from the 3-methylcholanthrene (P-450 3-MC) and beta-naphthoflavone (P-450 BNF) treated rats than with the phenobarbital preinduced cytochrome P-450 (P-450 BP). 3-OH-BP ad 9-OH-BP were the major phenolic products for both P-450 3-MC and P-450 BNF whereas the 3-OH-BP and 1-OH-BP were the major phenolic products for P-450 BP. The ratio of total phenols to diols was found to be 3.34, 4.85 and 0.70 for P-450 3-MC, P-450 BNF and P-450 PB. The major dihydrodiol generated by P-450 3-MC and P-450 BNF was 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene, whereas the 9,10-diol was the major diol from P-450 PB. The amount of 1,6- and 3,6-quinones produced was greater than the 6,12-quinone with the P-450 3-MC and P-450 BNF but all three quinones were produced in low and equal amounts by the P-450 PB. In respect to the percent metabolites formed at a given region of the BP, P-450 3-MC and P-450 BNF preferred oxidation at the 1, 3 positions, 6 position and the 7, 8 positions, whereas the P-450 PB preferred oxidation at the 4, 5 position. This study demonstrates the unique positional specificity of different forms of cytochrome P-450 which may regulate the balance between activation and detoxification pathways of polycyclic aromatic hydrocarbon metabolism.
Carcinogenesis 1982
PMID:Different patterns of benzo[a]pyrene metabolism of purified cytochromes P-450 from methylcholanthrene, beta-naphthoflavone and phenobarbital treated rats. 627 26

The ability of three purified forms of rat liver cytochrome P-450 to metabolically activate benzo[a]pyrene, trans-benzo-[a]pyrene-7,8-dihydrodiol, 2-aminofluorene, aflatoxin B1, dimethylnitrosamine, and a pyrolysis product of tryptophan(3-amino-1-methyl-5H-pyrido(4,3-b)indole) (Trp-P-2) to mutagenic products was examined using Salmonella typhimurium strains TA98 and G46 in a reconstituted monooxygenase system. The isozymes examined were cytochrome P-450-PB (the major phenobarbital inducible form), and the two major 3-MC inducible forms (cytochromes P-448(52) and P-448(55)). Cytochromes P-448(52) and P-448(55) preferentially metabolize 2-aminofluorene and Trp-P-2 to mutagenic products. However, only cytochrome P-448(55) metabolizes benzo[a]pyrene and its 7,8-dihydrodiol derivative to mutagenic products. Both cytochrome P-448(52) and P-448(55) metabolize aflatoxin B1 to mutagenic products at a much faster rate than cytochrome P-450-PB. Dimethylnitrosamine was not activated by any of the isozymes tested.
Carcinogenesis 1983
PMID:Specificity of rat liver cytochrome P-450 isozymes in the mutagenic activation of benzo[a]pyrene, aromatic amines and aflatoxin B1. 629 61

Neoantigen(s) induced on Syrian hamster cells during chemical carcinogenesis are also found on fetal and neoplastic hamster cells. 46 neoplastic cell lines independently isolated from colonies of 3-methylcholanthrene (3-MCA) in vitro-transformed hamster cells growing in semi-solid agar medium were assayed for expression of neoantigens recognized by hamster antisera to primary cultured late-term (15 days) hamster embryo cells treated for 18 h with 10 micrograms 3-MCA/ml. Ratios of the binding of this sera compared to solvent control sera ranged from 0.7 to 2.1 in terms of cpm bound. Only four of the 46 neoplastic cell lines exhibited significant (P less than 0.05) neoantigen expression. No correlation existed between the concentration of 3-MCA used to establish the neoplastic cell line and expression of the neoantigen(s). Absorption of the sera with these four highly reactive neoplastic cell lines and mid-term (10 days) embryo cells indicated that the neoantigen(s) recognized were common to the four reactive neoplastic cell lines and the mid-gestation fetal cells. The occurrence of early persistent immunogenic cell-surface alterations during in vitro carcinogenesis provides an approach to isolation of preneoplastic populations and provides potential target structures for the inhibition of carcinogenesis.
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PMID:Relationship of neoantigens induced by 3-methyl-cholanthrene treatment of Syrian hamster embryo cells to antigens expressed on fetal and 3-methyl-cholanthrene-transformed neoplastic cells. 664 56

The utility of C3/H/10T1/2 mouse embryo fibroblasts for the detection of carcinogenic substances has been limited by their apparent insensitivity to the oncogenic effects of direct-acting alkylating agents such as N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and procarcinogens such as aflatoxin B1 (AFB1). Because the process of C3H/10T1/2 transformation can be observed to proceed through discrete stages of initiation and promotion, we have considered the possibility that MNNG and AfB1 may only initiate C3H/10T1/2 transformation. Treatment of asynchronous C3H/10T1/2 cells with MNNG or AfB1 alone generally produced few transformed foci. If MNNG or AfB1 treatment was followed by the exposure of cells to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), numerous transformed foci were produced. Phorbol did not enhance transformation by either substance. MNNG and AfB1 thus appear to be initiating agents for transformation. TPA also enhanced the transformation of C3H/10T1/2 cells by low doses of 3-methylcholanthrene (3-MCA), but transformation by high concentrations of 3-MCA was inhibited by the presence of TPA. These studied suggest that the sensitivity of the C3H/10T1/2 transformation system to potential carcinogens can be dramatically heightened if the bioassay is conducted in the presence and absence of TPA.
Carcinogenesis 1982
PMID:Initiation of C3H/10T1/2 cell transformation by N-methyl-N'-nitro-N-nitrosoguanidine and aflatoxin B1. 680 61

We have reported that a strain of SHR have a selective depression of T-cell functions by aging, which may be due to an early appearance of natural thymocytotoxic autoantibody and a deficiency of thymic hormone. Results presented here showed that the tumor incidence in SHR by low doses of MCA was higher than those in WKA rats with normal T-cell functions. Depression of T-cell functions in SHR could be almost completely restored by allogeneic thymus grafts or injection of extracts from vaccinia virus-infected skin tissues (NSP). When immunological restoration was achieved, generation of killer T-cells against syngeneic tumor cells in SHR was induced and activity of NK cells against K-562 cells was significantly enhanced. Effect of thymus grafts or NSP on MCA-induced primary tumors in SHR was studied. Effect of thymus grafts or NSP on MCA-induced primary tumors in SHR was studied. The tumor incidence was significantly suppressed and average latent periods were also prolonged in SHR grafted with allogeneic thymus. The administration of NSP was not effective on tumor incidence but prolonged latent periods for developments of tumors. From these results, it is suggested that the SHR is a suitable animal model for investigation of role of cell-mediated immunity in carcinogenesis.
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PMID:[Immunological suppression of carcinogenesis in spontaneously hypertensive rats (SHR) with T-cell depression (author's transl)]. 697 36

Hepatocarcinogens cause marked biochemical changes in the liver at short intervals after administration. The studies described were designed to investigate the effects of hepatocarcinogens and hepatotoxicants on the microsomal mixed function oxidase system. DT-diaphorase and epoxide hydrolase. Following 5 day p.o. treatment of male F-344 rats with aflatoxin B1 (AFB), 2-acetylaminofluorene (AAF), technical grade dinitrotoluene (DNT), or 2,4-diaminotoluene, microsomal cytochrome P450 dependent enzyme activities were depressed while epoxide hydrolase activity was markedly elevated (3-8 times control). Diethylnitrosamine (DEN) given at 5 mg/kg/day and DL-ethionine at 1000 mg/kg/day failed to increase epoxide hydrolase. 3-Methylcholanthrene, methylnitrosourea, carbon tetrachloride, bromobenzene and vinyl chloride all failed to increase epoxide hydrolase activity. Using 3 daily i.p. injections, dose-response relationships for increases in epoxide hydrolase were generated for the hepatocarcinogens. With the exception of p-dimethylaminoazobenzene (DAB) and DEN, the carcinogens studied produced log-linear dose response curves for increase in epoxide hydrolase. Both DEN and DAB caused increases in epoxide hydrolase but classical sigmoidal dose-response curves were not obtained. The order of potency for increasing epoxide hydrolase was AFB greater than AAF greater than 2,6-dinitrotoluene greater than 3'-methyl-N,N-dimethyl-4-aminoazobenzene greater than DNT greater than 2, 4-dinitrotoluene. The slopes of the linear portions of the log dose-response curves were not statistically different from the slope of the dose-response curve obtained with AAF suggesting that structurally diverse carcinogens elicit increases in epoxide hydrolase by a common mechanism.
Carcinogenesis 1982
PMID:Effect of hepatocarcinogens on epoxide hydrolase and other xenobiotic metabolizing enzymes. 711 69

The effect of 200 micrograms doses of all-trans retinoic acid, given over a long duration (daily for 8 weeks, suspended for 3 weeks, then resumed daily for 4 weeks) or short duration (daily for 30 days), on the induction of fibrosarcomas in C57BL/6J mice by MCA was evaluated. A reduced level of carcinogenesis was observed with both lengths of retinoic acid treatment, since respective incidences of MCA fibrosarcomas were 63 and 61% of those in saline-treated controls. In other studies, the effect of all-trans retinoic acid on syngeneic growth of two experimental fibrosarcomas (B6 25 and B6 27, induced previously in C57BL/6J mice by MCA) was assessed. Retinoic-acid-treated mice were more resistant to higher doses of viable B6 27 (LD50 = 2.85) and especially B6 25 (LD50 = 3.80) than were corresponding saline- or corn-oil-treated controls (LD50 less than 2.0). The strength of resistance conferred by retinoic acid treatment thus varied considerably between these tumors, despite their common strain derivation and histopathological origin. Additional studies explored the effect on B6 27 growth of giving all-trans retinoic acid during either the sensitization or challenge stage of standard syngeneic immunogenicity tests. Mice given all-trans retinoic acid during sensitization displayed a markedly increased resistance to challenge with the immunospecific B6 27 tumor (LD50 = 5.30), compared to challenged controls that received saline (LD50 = 2.60) or corn-oil (LD50 = 2.55) during preimmunization. In contrast, when B6 27-preimmunized mice were treated with all-trans retinoic acid after challenge with homologous tumor, resistance to B6 27 (assessed by tumor growth rate and LD50 dose) was not increased but remained comparable to that of saline-or corn-oil-treated controls. While the mechanism(s) by which all-trans retinoic acid inhibits syngeneic growth of MCA tumors is unknown, our results support an immunostimulatory effect, evidenced by tumor resistance in both non-immune and specifically preimmunized syngeneic hosts.
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PMID:Effect of all-trans retinoic acid on induction, lethality and immunogenicity of murine methylcholanthrene-induced fibrosarcomas. 712 73

3-Methylcholanthrene (3-MC) pretreatment induces the liver microsomal 2-acetylaminofluorene (2-AAF) N-hydroxylase activity of C57BL6 responsive mice. The same pretreatment modifies this enzyme by significantly increasing its apparent Km value which, moreover, becomes protein concentration dependent. After 3-MC induction, the C57BL6 mouse liver microsomal 2-AAF N-hydroxylase is activated by paraoxon and 8-hydroxyquinoline. This last chemical does not, however, inhibit the microsomal metabolism of N-hydroxy-2-acetylaminofluorene (N-OH-2-AAF) as it does in the presence of guinea pig liver microsomes. The hypothesis is formulated that 3-MC pretreatment of C57BL6 mice induces not only cytochrome P448 dependent mixed function oxidase but also the synthesis of a microsomal protein which reversibly binds 2-AAF. Mutagenicity data are presented which corroborate this hypothesis. As in guinea pig liver microsomes, N-OH-2-AAF is further metabolized by both C57BL6 and DBA2 mouse liver microsomes. This metabolism is not inhibited by NaF which acts as an inhibitor of microsomal arylamidase. This is a possible contributing reason why 2-AAF is only weakly carcinogenic for mice.
Carcinogenesis 1982
PMID:Genetic differences in the enzymic properties of the aromatic hydrocarbon inducible N-hydroxylation of 2-acetylaminofluorene in mouse liver. 715 Dec 50

Chronic application of Piracetam decreases 3-methylcholanthrene-induced increased GABA content in the brains of rats and delays tumor appearance. The most active inhibitor of GABA-transaminase, amino oxyacetic acid (AOAA), increases the GABA content in the brain and appears to increase the tumor rate in 3-MC rats. Despite some reservations in view of results derived from investigations of only two compounds (3-MC and Piracetam) we suppose that a relation exists between effects on central nervous system and peripheral carcinogenesis. We will try to support our hypothesis further by using other compounds influencing the GABA-content of the brain.
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PMID:[Effects of 3-methylcholanthrene and 3-methylcholanthrene plus piracetam on the gamma-amino-butyric acid (GABA) content of several cerebral regions (author's transl)]. 730 84

Aspartyl and cysteine proteinases at distinct stages of carcinogenesis were analyzed in rat embryo fibroblasts, sequentially immortalized and transformed by 2 different genes: the early region of simian adenovirus SA7 and c-Ha-ras oncogene. The dynamics of expression and distribution of proteinases throughout the transformation process were examined. It was shown that in immortalized and transformed cells the activities of the aspartyl and cysteine proteinases were expressed to a variable degree and that the expression was dependent on cell-propagation time in vitro. The increase in activity both of cathepsin-D-like aspartyl proteinase and of cathepsin-L- and -B-like cysteine proteinases in cell lysates was correlated with the stages of fibroblast transformation (immortalization and tumorigenic transformation). In all cell types the major part of cysteine proteinases was localized inside the cell, while the cathepsin-D-like proteinase was apparently predominant among secreted proteinases. The cathepsin-L-like proteinase accounts for the major part of the cysteine-proteinase activity as measured by Z-Phe-Arg-MCA hydrolysis. We suggest that considerable portions of the cathepsin-D- and -L-like proteinases in all cell lines studied are secreted as a complex with inhibitor(s) and that inhibitor expression plays an important role in regulating the activity of cathepsin-D-like proteinase at different stages of transformation. Cathepsin-L-like proteinase is probably secreted in the precursor form.
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PMID:Proteolytic enzymes at various stages of oncogenic transformation of rat fibroblasts. I. Aspartyl and cysteine proteinases. 782 63


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