Genetic control of susceptibility to 3‐methylcholanthrene‐induced subcutaneous sarcomas

Kouri, Richard E.; Ratrie, Harry; Whitmire, Carrie E.

doi:10.1002/ijc.2910130515

Cited by 63 publications

(26 citation statements)

References 20 publications

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“…Strains which are sensitive to induction of P450 I by polycyclic aromatic hydrocarbons, termed 'responsive', were markedly more susceptible to the carcinogenicity of these chemicals when compared to strains of mice refractive to P450 I induction and termed 'non-responsive' [39]. A cytosolic receptor is present in the 'responsive' mice which binds avidly, but non-covalently, the inducing agent and mediates the induction of at least one of the two isozymes of the P450 I family, namely P450 I A1 [40].…”

Section: Discussionmentioning

confidence: 99%

Preferential induction of the rat hepatic P450 I proteins by the food carcinogen 2‐amino‐3‐methyl‐imidazo[4,5‐f]quinoline

Rodrigues

Ayrton

Williams

et al. 1989

European Journal of Biochemistry

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1. Administration of the food carcinogen, 2-amino-3-methyl-imidazo[4,5-flquinoline (IQ) to rats gave rise to significant dose-dependent increases in the microsomal 0-deethylations of ethoxycoumarin and ethoxyresorufin but had no effect on the 0-dealkylation of pentoxyresorufin and the NADPH-dependent reduction of cytochrome c, and decreased the N-demethylation of dimethylnitrosamine. Microsomal cytochrome b5 and total cytochrome P-450 levels decreased following the administration of the carcinogen.2. Hepatic microsomal preparations from IQ-treated animals were much more efficient than control in activating the premutagen 2-amino-6-methyldipyrido[l,2-u: 3',2'-dlimidazole to mutagenic intermediates in the Ames test.3. Immunoquantification of two of the major families of cytochrome P-450, namely P450 I and P450 I1 B, using ELISA techniques showed that treatment with IQ induced the apoprotein levels of the P450 I family but4. Immunoblot analysis employing polyclonal antibodies against P450 I revealed that IQ induced both isoenzymes of this family, namely P450 I A1 and A2.5. It is concluded that IQ is an inducer of the rat hepatic monooxygenases, selectively inducing the P450 I family as predicted by a computer-graphic analysis of its dimensions which showed that it is a large, essentially planar, molecule.The carcinogenicity of most chemicals is mediated, not by the parent form, but by reactive metabolic intermediates that readily interact with DNA initiating the process of tumourigenesis. By far the most prominent enzymes in the metabolic activation of chemical carcinogens are the ubiquitous monooxygenases whose terminal oxidase, cytochrome P-450, exists as a superfamily of proteins each of which confers to the system its characteristic substrate specificity [l].One of these families, namely P450 I (cytochromes P-448) appears to direct the metdbOhn of chemical carcinogens towards pathways that yield reactive species rather than inactive metabolites [2, 31. This family of isoenzymes is also involved in the activation of the aminoimidazo-azaarenes [4,5], which have been isolated from broiled fish and meat [6, 71. They are mutagens in a number of in vitro systems [8-111, activate a variety of oncogenes [12] and are potent animal carcinogens [I 3 -151. The prototype is IQ (2-amino-3-methylimidazo[4,5-flquinoline) whose activation proceeds through an initial N-hydroxylation to yield 2-amino-3-methyl-Nhydroxyimidazo[4,5-j~quinoline 1161, the proximate carcinogen, which undergoes further metabolism to generate the ultimate carcinogen [5]. The P450 I concentration in untreated animals is very small, immunologically calculated to be less than 5% of the total cytochrome P-450 content [17, 181, so that the activation of IQ is likely to be a minor pathway. However, many chemical carcinogens, such as the polycyclic The present study was therefore undertaken to establish if (a) IQ induces the rat hepatic monooxygenases, and (b) selectively induces the P450 I family that facilitates its activation. Since chemicals that inte...

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Section: Discussionmentioning

confidence: 99%

Preferential induction of the rat hepatic P450 I proteins by the food carcinogen 2‐amino‐3‐methyl‐imidazo[4,5‐f]quinoline

Rodrigues

Ayrton

Williams

et al. 1989

European Journal of Biochemistry

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“…Hepatic microsomal aryl hydrocarbon hydroxylase (AHH), a cytochrome P-448-dependent monooxygenase, is readily induced by 3-MC in several strains of mice, typified by the "responsive" C57BL/6J strain; in contrast, 3-MC does not induce AHH in nonresponsive strains, typified by the DBA/2J mice (5,6). Moreover, responsive mice are more susceptible than nonresponsive mice to the toxic (inflammation, fetotoxicity, primordial oocyte depletion) and carcinogenic effects of PAHs at organs/tissues in direct contact with the applied PAHs (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). The gene complex responsible for mediating the effects of PAHs has been designated the Ah locus which may comprise regulatory, structural, and possibly temporal genes.…”

Section: Introductionmentioning

confidence: 99%

Effects of structure on binding to the 2,3,7,8-TCDD receptor protein and AHH induction--halogenated biphenyls.

Safe

Bandiera²,

Sawyer³

et al. 1985

Environ Health Perspect

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The quantitative structure-activity relationships (QSARs) for polychlorinated biphenyl (PCB) congeners have been determined by comparing the ECQ, values for three in vitro test systems, namely, aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) induction in rat hepatoma H-4-II-E cells and competitive binding avidities to the rat cytosolic receptor protein (using 2,3,7,8-tetrachlorodibenzo-p-dioxin as a radioligand). For several PCB congeners that are in vivo inducers of rat hepatic microsomal AHH, there was a linear correlation between the -log EC.4 values for receptor and&the -log ECso values for AHH (or EROD) induction; moreover, a comparable linear relationship was observed between the -log EC.4 values for AHH and EROD induction. Previous in vivo studies have shown that the most active PCB congeners 3,3',4,4'-tetra-, 3,4,4',5-tetra-, 3,3',4,4',5-penta-, and 3,3',4,4',5,5'-hexachlorobiphenyl, cause many of the biologic and toxic effects reported for the highly toxic halogenated aryl hydrocarbon, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Moreover, the monoortho-substituted homologs of the four coplanar PCBs also elicit comparable in vivo biologic and toxic responses. It was evident from the QSARs for PCBs that there was an excellent correspondence between the in vivo and in vitro potencies of the individual PCB congeners.The effects of substituents on both receptor binding and AHH/EROD induction was determined for a series of 4'-substituted (X)-2,3,4,5-tetrachlorobiphenyls (where X = H, Cl, Br, I, OH, OCH,, NO2, COCH3, F, CF3, CH3, C2HA, i-C3H7, n-C4H, and t-C4H,). Not unexpectedly, there was a linear relationship between the -log ECso values for AHH and EROD induction, and these results confirm that both enzymatic oxidations are catalyzed by the same cytochrome P-450 isozyme(s). The effects of substituent structure on receptor binding for 12 substituents was subjected to multiple regression analysis which correlates the relative binding affinities of the compounds with the physical chemical characteristics of the substituents. The analysis gave the following equation: log (1/EC,0) = 1.53a + 1.47Th + 1.09 HB + 4.08 for n = 12, s = 0.18, r = 0.978; where n is the number of substituents, s is the standard deviation, r is the correlation coefficient, and af = electronegativity, -T = hydrophobicity (log P) and HB = hydrogen bonding capacity for the substituent groups. The data suggest that the latter three parameters facilitate the interaction between.the ligand and the cytosolic receptor protein. The effects of two lateral substituents on ligandreceptor interactions are not readily explained by the above relationship and may depend on other substituent physical chemical parameters.

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“…Since the incidence and the titer of hamster type C virus antigens in SV-40 induced tumor cells (7,10), as well as the murine leukemia gs antigen in SV-40-transfo:med Balb/e eells are known to increase in. subsequent in vivo transplanted tumors (12), the primary cell line was transplanted into six-week-old hamsters and from the resultant tumors a secondary cell line was established. Supernatant fluids from both cell lines, eolleeted 48 and 72 hours after formation of confluency, were clarified, subjected to high speed eentrifugation and the pellets tested for templated DNA polymerase activity.…”

Section: Resultsmentioning

confidence: 99%

Hamster endogenous retrovirus (HaER) isolated from SV-40 induced tumor cells

Goldschmied-Reouven

Yaniv

Perk

1983

Archives of Virology

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A hamster cell line obtained from a secondary transplanted SV-40-induced tumor was found to spontaneously release type C virus particles. The particles possessed all biochemical features characteristic of retroviruses and induced syncytium formation in XC cells but were not oncogenic for hamsters. Nucleic acid hybridization assays demonstrated that the isolated virus was an endogenous retrovirus of hamster, lacking sequence homology with mouse and other animal species.

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Genetic control of susceptibility to 3‐methylcholanthrene‐induced subcutaneous sarcomas

Cited by 63 publications

References 20 publications

Preferential induction of the rat hepatic P450 I proteins by the food carcinogen 2‐amino‐3‐methyl‐imidazo[4,5‐f]quinoline

Preferential induction of the rat hepatic P450 I proteins by the food carcinogen 2‐amino‐3‐methyl‐imidazo[4,5‐f]quinoline

Effects of structure on binding to the 2,3,7,8-TCDD receptor protein and AHH induction--halogenated biphenyls.

Hamster endogenous retrovirus (HaER) isolated from SV-40 induced tumor cells

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