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)

P450IIE1 was studied in rat hepatocyte foci and nodules from male Wistar rats, treated for 7 weeks with N-nitroso-morpholine (20, 40 and 80 mg/ml of drinking water). Livers were examined after 15, 23 and 31 weeks. Using specific anti-P450IIE1 IgG, different phenotypes of P450IIE1-altered foci were observed: (i) positive foci, predominant at early times and at the two lower dosages, (ii) negative foci and (iii) mixed-type foci consisting of P450IIE1-positive and -negative hepatocytes which were preponderant at 31 weeks. Immunoblotting of microsomes from livers containing foci and nodules obtained at week 31 of the experiment revealed a decrease in P450IIE1 level, which was correlated to decreased high affinity dimethylnitrosamine demethylase activity. The results suggest phenotypic heterogeneity of P450IIE1-altered foci with predominantly negative foci at later stages.
Carcinogenesis 1991 Dec
PMID:Immunochemical localization and functional characterization of cytochrome P450IIE1 in rat hepatocyte foci and nodules. 174 39

Disulfiram, widely used in avoidance therapy for alcohol abuse, has been shown to have protective effects against chemically induced toxicity and carcinogenesis. The purpose of this work was to elucidate the biochemical mechanisms of this protective action by examining its effects on cytochrome P450IIE1 and other related microsomal enzyme activities. When a dose of disulfiram was given intragastrically to rats, a very rapid decrease of N-nitrosodimethylamine (NDMA) demethylase activity, possibly due to the inactivation of P450IIE1, was seen. The loss of P450IIE1 protein from the microsomal membrane was observed at 18 hr after receiving disulfiram, but not within the first 5 hr after the treatment. P450IIB1, on the other hand, was induced markedly between 15 and 72 hr after the disulfiram treatment. The treatment, however, caused only moderate changes in some other P450 isozymes. Carbon disulfide, a putative metabolite of disulfiram, produced similar effects on P450IIE1, but with shorter duration. Carbon disulfide, however, did not induce P450IIB1. Diethyldithiocarbamate, a reductive product of disulfiram, was an inhibitor of P450IIE1 activity in vitro, and upon preincubation with microsomes, it produced an NADPH-dependent inactivation of NDMA demethylase activity. The results suggest that this or other metabolites of disulfiram are inhibitors of P450IIE1 and are responsible for the inactivation of P450IIE1 in vivo. Hepatotoxicity of NDMA or CCI4 in rats was blocked by pretreatment with disulfiram. The present work demonstrates that P450IIE1 was inhibited and inactivated by disulfiram, and this mechanism can account for many of the reported inhibitory actions of disulfiram against chemically induced toxicity and carcinogenesis.
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PMID:Effects of disulfiram on hepatic P450IIE1, other microsomal enzymes, and hepatotoxicity in rats. 185 Jan 73

The cytochrome P450-dependent reduction of Cr(VI) using reconstituted phospholipid vesicles containing purified preparation of various forms of rabbit and rat liver microsomal cytochrome P450 has been investigated. The alcohol-induced form of the rat, P450IIE1, was the most efficient enzyme, 7.2 +/- 0.40 nmol Cr/nmol P450/min, whereas the corresponding rates for rat P450IA1, rat IIB1, rabbit IIB4, rabbit IA2 and rabbit IIE1 were 1.7 +/- 0.09, 2.5 +/- 0.08, 1.6 +/- 0.08, 2.5 +/- 0.15 and 1.6 +/- 0.08 nmol Cr/nmol P450/min respectively. NADPH-cytochrome P450 reductase had Cr(VI) reductase activity which was dependent on enzyme concentration. Below 0.15 nmol P450 reductase/ml the sp. act. was low and constant, while at a higher concentration the activity was markedly dependent upon the amount of enzyme present. In a quantitative binding assay it was shown that binding of [51Cr]Cr(VI) to the catalytic enzymes was proportional to the enzyme concentration up to 0.8 nmol P450/ml, which caused binding of 70% of the total radioactivity. Analysis by SDS-PAGE and autoradiography exhibited binding to the individual catalytic proteins of [51Cr]Cr. EDTA treatment removed the radioactivity from the bands matching P450 and P450 reductase, indicating that Cr(III) is bound to the proteins. The reducing activity of both P450 and P450 reductase was potently inhibited by oxygen. The inhibitory effect of oxygen is not due to reoxidation of the reduced Cr and redox cycling. Rat P450IA1 ethoxycoumarin O deethylase activity was inhibited after preincubation with chromate (CrO4(2-). The P450 reductase inhibitor 2'-AMP stimulated the anaerobic P450 reductase dependent Cr(VI) reductase rate approximately 2-fold. Both CO and CCl4 inhibited the different P450 enzymes to various extents. With rabbit P450IIE1 CCl4 stimulated the Cr(VI) reduction approximately 4-fold, whereas the activity of the other enzymes was inhibited when the reconstituted system was incubated with CrO4(2-) and CCl4 prior to NADPH addition. Neither CO nor CCl4 affected the Cr(VI) reducing activity of the P450 reductase. The difference in CrO4(2-) reducing activity of the P450 enzymes and binding to the enzymes may be important for in vivo endoplasmic catalytic metabolism of CrO4(2-).
Carcinogenesis 1991 May
PMID:Reductive metabolism and protein binding of chromium(VI) by P450 protein enzymes. 190 91

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

Rat nasal cavity is one of the target organs for carcinogenesis induced by N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The present work investigated the metabolism of these nitrosamines by rat nasal microsomes, as well as the possible modulating factors. Microsomes prepared from rat nasal mucosa were efficient in metabolizing these nitrosamines. In general, the metabolism of the nitrosamines was slightly higher in 9-week-old rats than in 4-week-old animals, and there was no sex-related difference. Fasting of rats for 48 h, which is known to induce hepatic cytochrome P450IIE1 and NDMA metabolism, did not increase the nasal metabolism of NDMA, NDEA, or NNK. Pretreatment of rats with acetone, another inducer of hepatic P450IIE1, did not increase the metabolism of NDMA. Furthermore, it decreased the nasal metabolism of NDEA and NNK. Immunoinhibition studies suggest that, in the nasal mucosa, P450IIE1 is only partially responsible for the oxidation of NDMA and other P450 isozymes are responsible for the metabolism of NDEA. A single p.o. pretreatment of male rats with diallyl sulfide (DAS), a component of garlic oil, caused a significant decrease in the oxidative metabolism of NDEA and NNK in rat nasal mucosa. Whereas the nasal metabolism of NDMA was reduced by DAS pretreatment, there was no change in the amount of the nasal microsomal proteins immunoreactive with the antibodies against P450IIE1. The inhibitory effect of DAS on the nasal oxidative metabolism of NDMA, NDEA, and NNK was also observed in experiments in vitro. The results demonstrate the ability of nasal mucosa to metabolically activate these nitrosamines and the inhibition of this process by DAS, suggesting that DAS may be effective in inhibiting the related nasal tumorigenesis.
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PMID:Metabolism of carcinogenic nitrosamines by rat nasal mucosa and the effect of diallyl sulfide. 199 91

Several species of fish from the genus Poeciliopsis differ dramatically in their response to the carcinogen N-nitrosodiethylamine (NDEA). The differential induction of tumors among genotypes exposed to NDEA may, in part, result from differences in liver cytochrome P450pj activity (the piscine equivalent of mammalian P450j). Evidence for the existence of cytochrome P450pj activity and mRNA expression has been found in several Poeciliopsis genotypes (species and strains). Biochemical evidence suggests that a microsomal cytochrome P450 enzyme catalyzes the metabolism of NDEA to acetaldehyde and other intermediates in Poeciliopsis. This reaction was inhibited by carbon monoxide, and required molecular oxygen and reducing equivalents (NADPH). Differences were found in maximal activity as well as temperature optima among genotypes. Poeciliopsis, a livebearing fish from desert streams of northwestern Mexico, appears to have thermal optima for cytochrome P450pj activity between 25 and 30 degrees C depending on the genotype. Western blot analysis (using anti-rat P450IIE1 antibodies) detected a 55-60 kd band in microsomes isolated from rat and Poeciliopsis. Using a 49mer probe specific for rat cytochrome P450j, Northern blots revealed a 3.3 kb mRNA from livers of a Poeciliopsis genotype and rat, but none in muscle mRNA from either organism. S1 nuclease protection assays, using the same probe, revealed that a mRNA fragment protected by the probe against digestion was induced on exposure of the whole organism to ethanol (via uptake from the aquatic environment). The assays also demonstrated that ethanol treatments both induced and suppressed this mRNA, depending on concentration and exposure time.
Carcinogenesis 1991 Apr
PMID:Nitrosodiethylamine metabolism in the viviparous fish Poeciliopsis: evidence for the existence of liver P450pj activity and expression. 201 28

Cytochrome P450 is known to cause carcinogen activation and correspondingly increased cancer risk in animal models. In order to determine whether P450 in the colon may be involved in cancer development in the human, the human colon cell line LS174T was examined for the presence of various cytochromes P450. Two isozymes of P450 were identified in the human cell line. Expression of P450IA1 or IA2 was increased by treatment of the cell line with benzanthracene; the induction was demonstrated by an increase in RNA hybridizing to a probe for P450IA1 and by ethoxyresorufin deethylation activity. Western analysis of microsomes isolated from human colon tissue also demonstrated the presence of P450IA1, as well as a form which cross-reacted to an antibody to human P450IIC9. Another isozyme, P450IIE1, was identified by polymerase chain reaction amplification of RNA from LS174T cells. These results underscore the presence of cytochromes P450 in colonic tissue and provide a basis for the involvement of isozyme-specific P450 mediated reactions in carcinogenesis of the colon.
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PMID:Expression of two cytochromes P450 involved in carcinogen activation in a human colon cell line. 205

We report that, in a human cell line, human cytochrome P450IIA3 is capable of metabolizing aflatoxin B1, benzo[a]-pyrene, N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) to cytotoxic and mutagenic species. Cytochrome P450IIA3-mediated activation of NDMA and NDEA was compared with human cytochrome P450IIE1-mediated activation in the same cell system. P450IIE1 was more effective at activating NDMA than P450IIA3, while P450IIA3 was more effective at activating NDEA than P450IIE1. Whole cells and microsomal fractions obtained from control cells and from cells expressing the P450IIA3 cDNA were characterized for expression of P450IIA3. Microsomal coumarin 7-hydroxylase activity was some 40 times greater in the transfected cells than in the control cells and was catalyzed by a protein that was immunochemically related to the rat liver cytochrome P450IIA gene family. Immunoblot analysis demonstrated that this protein was readily detectable in transfected cells but barely detectable in control cells. We also report the DNA and deduced amino acid sequence of the P450IIA3 cDNA isolate used in this study. Our isolate encodes a protein 489 amino acids that is five amino acids shorter at the N terminus but otherwise identical to a previously reported human P450IIA3 cDNA sequence.
Carcinogenesis 1990 Aug
PMID:Human cytochrome P450IIA3: cDNA sequence, role of the enzyme in the metabolic activation of promutagens, comparison to nitrosamine activation by human cytochrome P450IIE1. 211 2

The mutagenicity of N-nitroso-N-benzyl-methylamine (NBzMA), N-benzyl-N-nitrosourea (BzNU) and N-methyl-N-nitrosourea (MNU) in Salmonella typhimurium strains was investigated. BzNU selectively mutated TA100 strain as compared to TA1535, whereas MNU showed an inverse strain response, an effect probably related to the fact that benzylation of DNA is a stronger inducer of SOS DNA repair than methylation, as indicated by the higher activity of BzNU in the SOS chromotest. Benzylation of bacterial DNA by NBzMA, as deduced from the differential strain responsiveness, contributed predominantly to its mutagenicity in the presence of liver preparation from untreated, Aroclor- or ethanol-treated rats. Since benzyl alcohol, a metabolite of NBzMA, was not mutagenic in S. typhimurium, it appears that benzyl carbonium cations responsible for the mutagenicity of NBzMA in TA100 are formed via cytochrome P450-mediated hydroxylation of the methyl group. Neither ferric-EDTA nor desferrioxamine altered the mutagenicity of NBzMA, suggesting that activation occurs mainly within the catalytic site of P450. Experiments with isozyme-specific monoclonal antibodies showed that P450IIE1 did not contribute to N-demethylation of NBzMA at either low or high substrate concentrations and that P450IA contributed only weakly. Debenzylation was catalysed predominantly by P450IA at high NBzMA concentration. Antibodies against rat liver P450IIB enhanced NBzMA mutagenicity in S. typhimurium TA1535 strain up to 17-fold at low substrate concentration, but were without effect at high concentration. In liquid incubation assays, a 100% GSH-dependent reduction of NBzMA mutagenicity was found with liver S9 from untreated Wistar rats. The reducing effect of GSH was less pronounced in the presence of liver S9 from BDVI or Fischer 344 rats.
Carcinogenesis 1990 Sep
PMID:Contribution of DNA methylation and benzylation to N-nitroso-N-benzyl-methylamine-induced mutagenesis in bacteria: effects of rat liver cytochrome P450 isozymes and glutathione transferases. 211 60

Cytochrome P450IIE1 is responsible for the metabolic activation of N-nitrosodimethylamine and a variety of other chemicals. Renal P450IIE1 was shown previously to be regulated by testosterone in C3H/HeJ and BALB/c mice. The present study investigated the distribution of cytochrome P450IIE1 in the kidneys of C3H/HeJ and BALB/c mice. The amount of P450IIE1 was immunotitrated by immunohistochemistry using polyclonal antibodies against rat P450IIE1. Strong immunoreactivity was identified mainly in the cortical tubules, including proximal tubules and some tubules. Weak immunoreactivity was also observed in the outer medulla when higher concentrations of antibodies were used. Much higher immunostaining was observed in male mice than in female mice when identical antibody dilutions were used. The renal P450IIE1 level in females was elevated to the same level as that in males 24 hr after administration of testosterone. The results showed a specific cellular localization of cytochrome P450IIE1 in mouse kidney. The findings may lead to a better understanding of the site-specific renal toxicity and carcinogenesis due to the activation of chemicals by cytochrome P450IIE1.
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PMID:Mouse renal cytochrome P450IIE1: immunocytochemical localization, sex-related difference and regulation by testosterone. 226 Sep 85


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