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)

Male F344 rats were treated with hepatocarcinogenic heterocyclic aromatic amines such as amino acid- and protein-pyrolysate components (Trp P-1, Trp P-2, Glu P-1, Glu P-2, A alpha C, MeA alpha C, IQ and MeIQx) and changes in microsomal cytochrome P-450 isozymes in the livers were examined by means of immuno-Western blotting using anti-rat cytochrome P-450 monoclonal antibodies. The results suggested that all chemicals tested induce cytochrome P-448 isozymes, particularly cytochrome P-448H (P-450IA2), which efficiently mediate mutagenic activation of the carcinogens. This was substantiated by the enzymatic analyses with the substrates showing different characters to rat cytochrome P-450 isozyme-mediated mutagenesis.
Carcinogenesis 1989 Jun
PMID:Hepatocarcinogenic heterocyclic aromatic amines that induce cytochrome P-448 isozymes, mainly cytochrome P-448H (P-450IA2), responsible for mutagenic activation of the carcinogens in rat liver. 272 Sep 4

Autoradiograms obtained after i.v. injection of the 14C-labelled carcinogenic glutamic acid pyrolysis product Glu-P-1 to mice and rats showed a pronounced uptake of radioactivity in the liver, kidney, thyroid and nasal mucosa. High concentrations of radioactivity were present in the bile and intestinal contents at short post-injection times. In the male rat, the Zymbal's gland and the preputial gland were identified as sites of high and specific binding at all post-injection times examined. The liver and nasal mucosa were identified as sites of retention of non-extractable radioactivity. In the pigmented mouse, Glu-P-1 and/or its metabolites were accumulated in melanin. Glu-P-1 is known to be activated by cytochrome P-448. Pretreatment with beta-naphthoflavone (a cytochrome P-448 inducer) did not change the tissue localization of radioactivity in either species except for the liver where the overall labelling was decreased. Neither did pretreatment of mice with the glutathione-depleting agent phorone change the distribution pattern significantly. However, combined pretreatments of mice with either phorone or beta-naphthoflavone and the cytochrome P-448 inhibitor 9-hydroxyellipticine resulted in an increased overall retention of radioactivity in the body.
Carcinogenesis 1989 Aug
PMID:Tissue localization of the carcinogenic glutamic acid pyrolysis product Glu-P-1 in control and beta-naphthoflavone-treated mice and rats. 275 27

The contribution of cytochrome P-450 isozymes to benzene metabolism in liver microsomes from fed, fasted, pyrazole-, phenobarbital (PB)- and ethanol-treated rats and in respective isocaloric controls was investigated using monoclonal antibodies (mAbs). Clone 1-7-1 mAb did not inhibit benzene metabolism, whereas clone 2-66-3 inhibited only in PB-induced microsomes at a high concentration of benzene (6.26 mM), and clone 1-91-3 mAb inhibited benzene metabolism in all cases. The degree of inhibition was as follows: fed congruent to isocaloric control congruent to PB less than fasted less than pyrazole congruent to ethanol. The pattern of inhibition was similar with clone 1-91-3 for low (0.23 mM) and high concentrations of benzene, except in PB-induced microsomes. Western blot analysis showed that clone 1-7-1 mAb did not bind any liver microsomal protein in the region of cytochrome P-450s, whereas with clone 2-66-3 a clear-cut band was seen only in liver microsomes from PB-treated rats, with clone 1-98-1, a band was detected in microsomes from all treated groups, in the following order: PB = isocaloric control less than fed less than fasted less than pyrazole less than ethanol. These results indicate that (i) cytochromes P-450b,e and P-450j contribute to benzene metabolism in rat liver; (ii) the former has a low affinity to benzene and is induced by PB; and (iii) P-450j has a high affinity to benzene and is induced by 1-day fasting, pyrazole and ethanol, but decreased by PB treatment.
Carcinogenesis 1989 Sep
PMID:Immunochemical characterization of cytochrome P-450 isozymes responsible for benzene oxidation in the rat liver. 276 63

The Long-Evans rat with a cinnamon-like coat color (LEC rat) is a mutant strain displaying hereditary hepatitis with severe jaundice. The age related difference in microsomal dealkylation of pentoxyresorufin and ethoxyresorufin was examined. The enzyme activity levels of pentoxyresorufin O-depentylase in LEC rats were decreased to 25% of the levels in control [Long-Evans rats with an agouti coat color (LEA rats)]. In contrast, ethoxyresorufin O-deethylase exhibited a much less marked difference between the strains. In parallel with these strain differences in enzyme activities, a decrease in phenobarbital (PB) inducible P450 isozymes, mainly P450b and P450e, was observed by Western blot analysis. The level of P450PB in LEC rats was more markedly depressed than in the LEA strain. On the other hand, microsomes from uninduced LEC rat liver had more 3-methylcholanthrene (MC) inducible P450MC, mainly P450c and P450d, than microsomes from LEA rat liver and these isozymes in the LEC were markedly induced by 3-methylcholanthrene treatment. The great difference in cytochrome P450PB content of the liver microsomes between LEC and LEA rats and the maintained constitutive levels of hepatic cytochrome P450MC in the LEC rats suggest a possible role of these cytochrome isozymes in the onset of spontaneous hepatitis and hepatoma.
Carcinogenesis 1989 Nov
PMID:Selective expression and induction of cytochrome P450PB and P450MC during the development of hereditary hepatitis and hepatoma of LEC rats. 280 35

Aromatic amines are well known as occupational carcinogens and are found in cooked foods, tobacco smoke, synthetic fuels, and agricultural chemicals. For the primary arylamines, metabolic N-oxidation by hepatic cytochromes P-450 is generally regarded as an initial activation step leading to carcinogenesis. The metabolic activation of 4-aminobiphenyl, 2-naphthylamine, and several heterocyclic amines has been shown recently to be catalyzed by rat cytochrome P-450ISF-G and by its human ortholog, cytochrome P-450PA. We now report that human hepatic microsomal caffeine 3-demethylation, the initial major step in caffeine biotransformation in humans, is selectively catalyzed by cytochrome P-450PA. Caffeine 3-demethylation was highly correlated with 4-aminobiphenyl N-oxidation (r = 0.99; P less than 0.0005) in hepatic microsomal preparations obtained from 22 human organ donors, and both activities were similarly decreased by the selective inhibitor, 7,8-benzoflavone. The rates of microsomal caffeine 3-demethylation, 4-aminobiphenyl N-oxidation, and phenacetin O-deethylation were also significantly correlated with each other and with the levels of immunoreactive human cytochrome P-450PA. Moreover, a rabbit polyclonal antibody raised to human cytochrome P-450PA was shown to inhibit strongly all three of these activities and to inhibit the N-oxidation of the carcinogen 2-naphthylamine and the heterocyclic amines, 2-amino-6-methyldipyrido-[1,2-a:3',2'-d]imidazole and 2-amino-3-methylimidazo[4,5-f]-quinoline. Human liver cytochrome P-450PA was also shown to catalyze caffeine 3-demethylation, 4-aminobiphenyl N-oxidation, and phenacetin O-deethylation. Thus, estimation of caffeine 3-demethylation activity in humans may be useful in the characterization of arylamine N-oxidation phenotypes and in the assessment of whether or not the hepatic levels of cytochrome P-450PA, as affected by environmental or genetic factors, contribute to interindividual differences in susceptibility to arylamine-induced cancers.
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PMID:Human cytochrome P-450PA (P-450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines. 281 53

NAD(P)H:Quinone oxidoreductase (QR) is a widely-distributed enzyme that promotes obligatory two-electron reductions of quinones and thereby protects cells against the cytotoxicity of quinones and their metabolic precursors. QR is induced by a wide variety of chemoprotectors in many animal tissues as well as in the Hepa 1c1c7 murine hepatoma cell line. Such inducers fall into two families: dual inducers (e.g. polycyclic aromatics, azo dyes, beta-naphthoflavone) that elevate QR as well as cytochrome P1-450, and selective inducers of QR (e.g. tert-butylhydroquinone and other redox-labile diphenols). Induction by the first family of inducers depends on binding to the Ah (Aryl hydrocarbon) receptor and the associated expression of a functional cytochrome P1-450 enzyme, whereas the induction by redox-labile diphenols does not appear to be receptor-mediated. In order to analyze the possible role of the cytochrome P1-450 system in the induction of QR, we examined this process in the Hepa 1c1c7 cells and in four mutants of this cell line that are defective in the induction or expression of functional cytochrome P1-450. tert-Butylhydroquinone was an effective inducer of QR in all of the cell lines, and this process does not, therefore, depend on a functional cytochrome P1-450 enzyme. In contrast, azo dyes and polycyclic aromatics induce QR in the parent cell line but not in the various types of cytochrome P1-450-defective mutants. We conclude that the Ah receptor and cytochrome P1-450 function are involved in the induction of QR by certain azo dyes and polycyclic aromatics, but not by phenolic antioxidants.
Carcinogenesis 1987 Oct
PMID:Role of cytochrome P1-450 in the induction of NAD(P)H:quinone reductase in a murine hepatoma cell line and its mutants. 282 Jun 4

The effect of oral administration of a Prudhoe Bay crude oil (PBCO) to male rats (PBCO, 2.6 g/kg body weight, daily) for 5-12 days on hepatic and renal microsomal monooxygenase activities and peroxisomal beta-oxidation has been investigated. PBCO administration leads to liver enlargement. This is associated with induction of microsomal cytochrome P-450 levels (1.6- to 2.0-fold) and dependent mixed-function oxidase activities (7-ethoxyresorufin-O-deethylase and 7-pentoxyresorufin-O-depentylase, representing cytochrome P-450I and cytochrome P-450IIB isoenzymes respectively, 9- to 15-fold; omega-oxidation of lauric acid representing the cytochrome P-450IVA1 isoenzyme, 1.4- to 1.5-fold) along with peroxisomal beta-oxidation (palmitoyl CoA oxidation, 2- to 5-fold). It was observed that rats exposed to PBCO showed an increase in renal microsomal cytochrome P-450 content (1.6- to 2.3-fold), cytochrome P-450I activity (5- to 8-fold) and omega-oxidation activity (1.3- to 1.4-fold). However, renal peroxisomal beta-oxidation was unaltered. Serum total triglycerides were lowered by 41-46% after PBCO exposure. These results suggest that induction of peroxisomal beta-oxidation and possibly mono-oxygenases may be related to the carcinogenic/tumorigenic potential of crude oil.
Carcinogenesis 1989 Feb
PMID:Effect of a Prudhoe Bay crude oil on hepatic and renal peroxisomal beta-oxidation and mixed-function oxidase activities in rats. 291 77

We have demonstrated that the human cytochrome P1-450 gene can be transfected into the AHH-1 human lymphoblastoid cell line using the pHEBo vector and hygromycin selection. The transfected gene was expressed when regulatory sequences derived from the herpes simplex virus thymidine kinase gene were incorporated in appropriate orientations. Gene expression was monitored at the enzyme level using assays for 7-ethoxyresorufin deethylase, 7-ethoxycoumarin deethylase and benzo[a]pyrene hydroxylase activities. Bulk transformed cell populations had 2- to 3-fold more of these enzyme activities compared with control populations. Subclones of the bulk population expressing still higher levels of 7-ethoxyresorufin deethylase activity were also obtained. Expression of the transfected cytochrome P1-450 gene was stable for 20-30 days in the presence of hygromycin B. The transformed cell populations were found to be suitable for use in gene locus mutation assays and the mutagenicity of aflatoxin-B1 and 2-acetylaminofluorene (AAF) were examined. Aflatoxin-B1 was found to be 2-3 times more mutagenic to cells bearing the transfected cytochrome P1-450 activity as compared with control cells. In contrast, no difference in AAF mutagenicity was observed. Analysis of the AAF metabolite profile indicated that cells expressing the transfected cytochrome P1-450 gene produced 8-fold more N- and 7-hydroxy-AAF than control cells. The similarity in mutagenic responses between control cells and cells bearing the transfected cytochrome P1-450 gene may be due to the low deacetylase activity of AHH-1 cells. These observations indicate that this vector and expression system are suitable for introducing novel metabolic activities into the AHH-1 cell line.
Carcinogenesis 1989 Feb
PMID:Transfection of a human cytochrome P-450 gene into the human lymphoblastoid cell line, AHH-1, and use of the recombinant cell line in gene mutation assays. 291 81

Cell lines were established which produce replication-defective ecotropic and amphotropic host range recombinant retroviruses containing the cDNA for mouse cytochrome P3-450 as well as the bacterial Neo gene for G418 resistance. The G418-resistant clones derived from virus-infected cultures were analyzed for the expression, subcellular localization, and catalytic activities of the cytochrome P3-450. Southern blot analysis of the genomic DNAs indicates that the viral DNA was stably integrated into the cellular DNA. Western blot analysis of the proteins showed that the size of the constitutively expressed product was Mr 54,000, indistinguishable from the cytochrome P3-450 found in mouse liver microsomes. Spectral characterization of the P3-450 proteins indicates that the newly synthesized apoprotein incorporated heme and integrated into the microsomes. Enzymatic analysis of the cell homogenates in vitro and of the dividing cells in situ showed very high acetanilide hydroxylase activity and very low aryl hydrocarbon hydroxylase activity, a diagnostic feature of the cytochrome P3-450. The precise transmission of the recombinant retroviral sequences into the target cells and the exceptional fidelity of expression of the enzyme in cells will allow the analysis of an increasing number of cloned genes of cytochrome P-450s by defining the individual enzyme specificities, their physiological role in cells, and consequences of their functional expression, such as in toxicity, mutagenesis, and carcinogenesis.
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PMID:Transduction of cytochrome P3-450 by retroviruses: constitutive expression of enzymatically active microsomal hemoprotein in animal cells. 291 41

Competition between a hydroxylated metabolite and the parent polycyclic aromatic hydrocarbon (PAH) for metabolism at cytochromes P-450 may result in the generation of hydroxylated dihydrodiol epoxides. The effectiveness of the competition between 7-hydroxymethyl-12-methylbenz[a]anthracene (7HOMMBA) or 12-hydroxymethyl-7-methylbenz[a]anthracene (12HOMMBA) and 7,12-dimethylbenz[a]anthracene (DMBA) is highly dependent on the form(s) of cytochrome P-450 in the microsomes. The inhibitory effects of exogenously added 7HOMMBA or 12HOMMBA on DMBA metabolism were 30- to 50-fold greater in 3-methylcholanthrene (MC)-induced rat liver microsomes (Ki = 0.4 microM) compared to either uninduced or phenobarbital (PB)-induced liver microsomes (Ki = 14 and 11 microM, respectively). Similarly, product inhibition of total DMBA metabolism by metabolites generated in situ was significant only in MC-induced liver microsomes (Ki' = 2.5 microM). Metabolism of 7HOMMBA in these microsomes was strongly restricted by an unusual substrate inhibition derived from the inhibitory binding of a second molecule of 7HOMMBA. This same phenomenon was observed with reconstituted cytochrome P-450c but not with PB-induced or uninduced microsomes. Complex formation by binding of DMBA, 7HOMMBA, and 12HOMMBA to purified P-450c reconstituted in phospholipid micelles was determined by optical spectroscopy and fluorescence quenching. Binding affinities of both the 7HOMMBA and 12HOMMBA (Kd = 95 and 110 nM, respectively), were 2.5-fold higher compared to that of DMBA (Kd = 265 nM). These results provide a first demonstration that hydroxylation of a PAH can lead to preferential metabolism through an increased affinity for cytochrome P-450.
Carcinogenesis 1986 Jun
PMID:Selective interactions of cytochromes P-450 with the hydroxymethyl derivatives of 7,12-dimethylbenz[a]anthracene. 308 67


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