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)

Polycyclic aromatic hydrocarbon (PAH)-induced C3H/10-T1/2/CL8 mouse embryo fibroblasts (10T1/2) and mouse hepatoma-derived Hepa 1c1c7 cells (Hepa-1), exhibit comparable total cytochrome P450 levels and total PAH-metabolizing activities but very different distributions of PAH metabolites. Based on anti-P450IA1-IgG inhibition data, P450IA1 contributes essentially all PAH metabolism in Hepa-1 microsomes but is not involved in PAH metabolism by 10T1/2 cells. In addition, the microsomal epoxide hydratase (EHm) in Hepa-1 cells is far less effective in dihydrodiol (diol) formation compared to that in 10T1/2 microsomes [Pottenger, L.H. and Jefcoate, C.R. Carcinogenesis, 11, 321-327 (1990)]. In the present study, the levels of expression of P450IA1 and EHm proteins and the corresponding mRNAs, both prior to and following exposure to benz[a]anthracene (BA) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), have been correlated with microsomal PAH metabolism by each cell type. In 10T1/2 cells, P450IA1 protein (56 kd) and mRNA (2.6 kb) were detectable at extremely low levels in only two of five cell preparations and then only after maximum induction by TCDD and BA. Thus although 10T1/2 cells contain functional Ah receptors, their capacity to induce P450IA1 is highly suppressed, representing at most 2% of the total P450. TCDD (10 nM) was 4-fold more effective than BA (10 microM) in inducing P450IA1 mRNA, while the levels of immunodetectable protein were comparable. An even greater discrepancy between P450IA1 mRNA and protein levels was seen in BA-induced Hepa-1 cells, where a 4-fold increase in mRNA was paralleled by a 20-fold increase in protein. This difference is probably due to the greater effect of BA depletion on mRNA compared to protein levels. In 10T1/2 cells, BA and TCDD were equally effective at increasing expression of an unidentified 1.9 kb mRNA sequence that blotted very weakly with the P450IA1 cDNA probe. The expression of this mRNA was independent from that of P450IA1. A similar band was visible in Hepa-1 cells less than 1% of the P450IA1 mRNA. EHm mRNA was almost 3-fold higher in 10T1/2 compared to Hepa-1 cells and was unaffected by cell treatments. In Hepa-1 cells, BA and TCDD elevated EHm protein and hydrating activity to levels comparable to those expressed in 10T1/2 cells. It is, therefore, suggested that the relative ineffectiveness of Hepa-1, compared to 10T1/2 EHm, to hydrate low levels of PAH-epoxides is due to differences between the two proteins or their disposition in the microsomal membrane.
Carcinogenesis 1990 Oct
PMID:Differences in the modulation of P450IA1 and epoxide hydratase expression by benz[a]anthracene and 2,3,7,8-tetrachlorodibenzo-p-dioxin in mouse embryo versus mouse hepatoma-derived cell lines. 220 84

Mice but not rats are susceptible to 4-vinylcyclohexene (VCH)-induced ovarian toxicity and carcinogenicity. This is due in part to a 4- to 6-fold greater rate of hepatic microsomal bioactivation of VCH to the ovotoxicant VCH-1,2-epoxide. The biochemical basis for this difference was investigated in microsomes using enzyme induction, enzyme inhibition with chloramphenicol or specific inhibitory antibodies, and correlation with marker steroid hydroxylase activities to associate VCH epoxidation with particular cytochrome P450 forms. Testosterone 6 beta- and 15 alpha-hydroxylase activities and VCH epoxidation were decreased in microsomes from chloramphenicol-treated mice, initially suggesting the possible involvement of P450IIIA and P450IIA forms in VCH metabolism. Although both testosterone 6 beta-hydroxylase and VCH epoxidase activities were increased by dexamethasone treatment (P450IIIA inducer), anti-rat P450IIIA IgG inhibited testosterone 6 beta-hydroxylase (68%) but not VCH epoxidase activity. These latter results do not support the involvement of mouse P450IIIA forms in VCH epoxidation. However, results were obtained which indicated that mouse P450IIA forms are involved in VCH epoxidation. In microsomes from untreated female mice VCH epoxidase activity was inhibited 48% by antibodies to mouse P45015 alpha (P450IIA3) at a concentration that inhibited testosterone 15 alpha-hydroxylase activity by 86%. No protein immunochemically related to mouse P45015 alpha was detected in female rat hepatic microsomes. VCH epoxidation by hepatic microsomes was increased in female mice and rats by phenobarbital treatment and was inhibited by approximately one-third by anti-rat-P450IIB1 IgG in microsomes from untreated animals of both species. Furthermore, microsomal VCH epoxidase and testosterone 16 alpha-hydroxylase activities were lower (34%) in female 129/J mice (deficient in constitutive expression of P450IIB forms) than in B6C3F1 mice. These results suggested partial involvement of P450IIB forms in the microsomal epoxidation of VCH. Therefore, P450 forms IIA and IIB account for the majority of VCH bioactivation in female mouse liver, which explains in part the susceptibility of mice to VCH-induced ovarian toxicity and carcinogenicity.
Carcinogenesis 1990 Nov
PMID:The biochemical basis for the species difference in hepatic microsomal 4-vinylcyclohexene epoxidation between female mice and rats. 222 27

Rat liver microsomes metabolized the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) to the genotoxic metabolite 2-hydroxamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (2-hydroxamino-PhIP) and to the detoxified product 2-amino-4'-hydroxy-1-methyl-6-phenylimidazo[4,5-b]pyridine (4'-hydroxy-PhIP). A 25-fold higher rate of metabolism was measured in microsomes from polychlorinated-biphenyl-treated rats (94 nmol/mg proteins/30 min) in comparison with those from untreated rats. Other effective inducers of PhIP metabolism were beta-naphthoflavone and isosafrole (ISF), whereas phenobarbital was ineffective. About twice as much 2-hydroxamino-PhIP as 4'-hydroxy-PhIP was formed in microsomes irrespective of the inducer the rats had been treated with. The metabolism was dependent on NADPH and was abolished by the cytochrome P450 inhibitor alpha-naphthoflavone. In a reconstituted enzyme system purified rat cytochrome P450 IA2 (P450ISF-G) had the highest N-hydroxylation rate (30 nmol/nmol P450/30 min) closely followed by the rat cytochrome P450 IA1 (P450BNF-B). Less activity was seen with rat P450 IIC11 (P450UT-A) and rabbit P450 IA2 (P450 LM4). Rat P450 IIE1 (P450j), P450 IIB1 (P450PB-B) and rabbit P450 IIB4 (P450 LM-2) and P450 IIE1 (P450 LM3a) were essentially inactive. Rat P450 IA1 (P450BNF-B) produced five times more 4'-hydroxy-PhIP (32 +/- 2 nmol/nmol P450/30 min) than did P450 IA2 (P450ISF-G). Hence, the measured ratio of activation to detoxication for rat P450 IA2 (P450ISF-G) enzyme was 7-fold higher than that of the other active P450 enzymes.
Carcinogenesis 1990 Mar
PMID:Differential rates of metabolic activation and detoxication of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine by different cytochrome P450 enzymes. 231 Nov 93

The hypothesis has been put forward that genotoxic aromatic amines which induce the P450 I family of haemoproteins, the major enzyme involved in their bioactivation, are more likely to be carcinogenic when compared to those chemicals that fail to do so. Induction of the hepatic P450 I family of proteins by carcinogenic aromatic amines and their non-carcinogenic isomers and analogues was investigated in the rat and correlated to their carcinogenic potential. The activity of the P450 I A1 protein was monitored by the O-deethylation of ethoxyresorufin and of the P450 I A2 by the activation of the premutagen Glu-P-1 to mutagenic intermediates in the Ames test. Results were always confirmed immunologically in Western blots employing antibodies to rat P450 I A1 which recognize both proteins of the P450 I family. With all groups of chemicals used in the present study, the members displaying carcinogenicity were always the more potent inducers, while the non-carcinogenic isomers or analogues displayed little or no induction. It appears that a relationship exists between the carcinogenicity of aromatic amines and their ability to induce hepatic P450 I activity.
Carcinogenesis 1990 May
PMID:The induction of P450 I proteins by aromatic amines may be related to their carcinogenic potential. 233 9

The cytochrome P450-dependent metabolism of the heterocyclic amine mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) has been determined. We investigated the in vitro metabolism of PhIP by polycyclic hydrocarbon-induced mouse and rabbit liver microsomes, and by purified rabbit liver P450 isozymes. Following a 60 min incubation, 3-methylcholanthrene-induced mouse microsomes converted 36% of the PhIP to two major metabolites, N-hydroxy-PhIP and 4'-hydroxy-PhIP, with 43% total metabolism. Rabbit P450 form 6 and form 4 produced the same two major metabolites (20 and 5% total metabolism respectively). Additional metabolites were produced in low yields and amounts varied depending on the isozyme used (1-5%). Metabolites were not detected in incubations of PhIP with P450 forms 2 and 3C. N-Hydroxy-PhIP was found to be directly mutagenic to Salmonella TA98, while the 4'-hydroxy-PhIP was not mutagenic either with or without additional metabolic activation. These data suggest that the cytochrome P450IA isozymes are involved in the metabolism of PhIP by rabbit liver and that formation of N-hydroxy-PhIP is involved in the mutagenicity of PhIP.
Carcinogenesis 1990 Jun
PMID:Metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) by liver microsomes and isolated rabbit cytochrome P450 isozymes. 234 68

We report the effects of several inducers of P450 metabolizing enzymes on DNA adduct formation by 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in C57BL/6 mice. We also examined the role of N:O-acetylation and the nitrenium ion in the genotoxicity of MeIQx, since these have been implicated in the activation of other aminoimidazoazaarenes (AIA) to DNA reactive species. Mice were given phenobarbital (PB), Aroclor 1254, beta-naphthoflavone (BNF) or corn oil, i.p., followed 3-5 days later with oral administration of MeIQx. Induction of Aroclor and BNF produced DNA with 8-fold more adducts than either the corn oil-alone or PB-treated animals. Both corn oil-alone and PB-treated animals were similar. Four major adducts were found in all cases with no differences among inducers as judged by co-chromatography. Azido-MeIQx induced calf-thymus-DNA adducts produced identical adduct profiles to those seen for the mouse DNA. Similar adduct profiles were obtained from Salmonella TA98, and the nitroreductase deficient strains (TA98NR and TA98/1,8-DNP6) exposed to MeIQx in the presence of Aroclor-induced-mouse-liver S9. Adduct frequencies in TA98/1,8-DNP6 were significantly lower than in TA98 and TA98NR. The data described in this report demonstrate that induction quantitatively increases adduct numbers but does not affect the types of DNA damage. These data also suggest that the same DNA reactive intermediates are formed in vivo as in vitro and support the hypothesis that the metabolism of MeIQx involves the P450I family of isozymes, N:O-acetyltransferases and possibly a nitrenium ion. The application of radioanalytic scanners for quantitation of 32P-postlabelling adduct maps is described.
Carcinogenesis 1990 Jan
PMID:Role of metabolism on the DNA binding of MeIQx in mice and bacteria. 240 59

A variety of cytochromes P450 have been implicated in the hepatic metabolism of benzo[a]pyrene (BP), including forms that are constitutively expressed and those that are highly inducible. In the present study the metabolism of BP to organic solvent-soluble derivatives by eight forms of cytochrome P450 isolated from rat liver and by a series of 11 human liver microsomal samples was investigated. The relative contribution of specific P450 forms to the human hepatic metabolism was evaluated. A 4-fold variation in formation of total organic solvent-soluble BP metabolites was observed, as well as differences in the regio- and stereoselectivity of this metabolism between the three individuals studied. The levels of expression of cytochromes P450 from five gene sub-families, as determined by Western blot analysis, did not show any correlation with the rate of BP metabolism to organic solvent-soluble derivatives in these livers. No reduction in metabolism was observed in three livers in which either the debrisoquine P450 (P450IID1) was not expressed or bufuralol 1-hydroxylase activity was low. Of six different antibodies to forms of rat liver P450 tested, only those to P450s MC1a (P450IA2), MC1b (P450IA1) and UT1 (P450IIA1) consistently inhibited BP metabolism. This inhibition was generally limited and rarely exceeded 30%. An antibody to cytochrome P450 PB3a (P450IIB1) did, however, inhibit the formation of metabolites at the 4,5- and 9,10-positions of BP by microsomal fractions of livers from one individual who had been receiving the drug phenytoin. These data indicate that several forms of P450 in human liver are involved in the metabolism of BP and that both constitutively expressed as well as inducible forms are important in its disposition in man.
Carcinogenesis 1989 Oct
PMID:Relative contribution of various forms of cytochrome P450 to the metabolism of benzo[a]pyrene by human liver microsomes. 279 Nov 99

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

Female rats received N-nitrosomorpholine to produce altered cell foci (potential cancer pre-stages) in the liver, followed by phenobarbital (PB) for 2 weeks. As indicators of adaptive responses we measured DNA synthesis cumulatively by infusion of [3H]thymidine for the entire period of PB treatment, and cytochrome P450-PB by immunocytochemistry on histological liver sections. Altered cell foci were identified by expression of gamma-glutamyltransferase (gamma-GT), and/or altered morphology. The following results were obtained. In normal parts of the liver PB induced DNA replication only in association with expression of P450-PB; both responses were restricted to the pericentral area of the liver lobule. In foci, PB treatment led to enhanced DNA synthesis. Furthermore, PB caused a 3-fold increase in the number of foci expressing cytochrome P450-PB, gamma-GT or both. Cumulative determination of DNA synthesis showed that this increase did not result from selective proliferation of single initiated cells. It is concluded that in foci also PB can induce expression of the adaptive increases in cytochrome P450-PB and DNA synthesis. Foci show the responses to PB more readily than normal hepatocytes, and irrespective of their position within the liver lobule. These findings suggest that expression of adaptive responses to inducing tumor promoters is facilitated in altered foci.
Carcinogenesis 1986 Oct
PMID:Facilitated expression of adaptive responses to phenobarbital in putative pre-stages of liver cancer. 287 9

Foci of atypical acinar cells observed in male rats 1 year after a single injection of hydroxyaminoquinoline 1-oxide (HAQO) were assessed immunohistochemically for altered expression of a number of enzyme forms considered to play important roles in drug metabolism. The pancreatic lesions, classified as of either basophilic or eosinophilic type on histological appearance, demonstrated distinctive patterns of altered enzyme phenotype. On the one hand, the basophilic foci composed of enlarged cells/nuclei with very prominent nucleoli were characterized by increase in GST-P, G6PD and P450 PB1 and MC2 forms. The eosinophilic type, in contrast, comprised smaller cells demonstrating elevated P450 MC1 and PB1 but not MC2, normal G6PD and strong GST-P binding limited only to a proportion of the nuclei. Both shared decreased GGT and almost total lack of GST-B positive connective tissue and ductular elements. Apparent islet cell lesions and normal islet tissue were characterized by a distinct enzyme phenotype strongly positive for all P450 species investigated. The results indicate that HAQO-induced putative preneoplastic pancreatic lesions, like equivalent carcinogen associated with focal populations in liver, kidney and ductular pancreas, demonstrate a non-random altered expression of specific drug metabolizing enzyme species.
Carcinogenesis 1987 Aug
PMID:Altered drug metabolizing potential of acinar cell lesions induced in rat pancreas by hydroxyaminoquinoline 1-oxide. 288 32


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