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The Journal of Investigative Dermatology Feb 1976Mouse skin contains a NADPH-dependent, aryl hydrocarbon hydroxylase (AHH), which is inducible by polycyclic aromatic hydrocarbons. In general, unsubstituted polycyclic...
Mouse skin contains a NADPH-dependent, aryl hydrocarbon hydroxylase (AHH), which is inducible by polycyclic aromatic hydrocarbons. In general, unsubstituted polycyclic hydrocarbons caused a greater induction of epidermal AHH than substituted one (1,2,3,4-dibenzanthracene greater than 1,2,5,6-dibenzanthracene greater than benz (a)anthracene equal 3-methylcholanthrene greater than 7,12-dimethlbenz (a)anthracene) which did not correlate with their ability to initiate tumors in mouse skin. Two different techniques were used to isolate epidermis and similar results were obtained with both. However, the technique of isolating epidermis using a mild heat treatment required that the temperature be maintained at 52 degrees C for 30 sec. If the temperature was raised to 54 degrees C or above, there was a large reduction in the AHH activity. Isolated epidermis has 4 to 5 times the AHH activity as dermis and about twice that of whole skin. This was true for control mice or mice in which AHH was induced by pretreatment with benz(a)anthracene.
Topics: Animals; Aryl Hydrocarbon Hydroxylases; Benz(a)Anthracenes; Enzyme Induction; Histological Techniques; In Vitro Techniques; Methylcholanthrene; Mice; NADP; Skin; Temperature
PubMed: 1447
DOI: 10.1111/1523-1747.ep12481449 -
British Journal of Cancer Dec 1965
Topics: Adenofibroma; Adenoma; Animals; Benz(a)Anthracenes; Carcinoma, Intraductal, Noninfiltrating; Female; Fluorenes; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Methylcholanthrene; Rats
PubMed: 4285918
DOI: 10.1038/bjc.1965.96 -
British Journal of Cancer Oct 1973Growth of syngeneic transplants of a 3-methylcholanthrene induced rat sarcoma was suppressed when tumour cells were injected in admixture with BCG. Rejection of these...
Growth of syngeneic transplants of a 3-methylcholanthrene induced rat sarcoma was suppressed when tumour cells were injected in admixture with BCG. Rejection of these mixed inocula resulted in the suppression of growth of a simultaneous challenge with cells of the same tumour at a contralateral subcutaneous site and conditions for immunotherapy were evaluated with respect to the maximum tumour cell challenge rejected and the optimum time of treatment. These studies established that viable tumour cells were more effective than radiation attenuated cells for the immunizing stimulus. Also, the maximum tumour challenge totally rejected in this way was of the order of 10(6) cells, and with this rapidly growing tumour, treatment had to be initiated within 4 days of tumour injection. These observations are relevant to current proposals for adjuvant immunotherapy of human malignant disease where conditions of minimal residual disease are not being fulfilled.
Topics: Animals; BCG Vaccine; Female; Immunotherapy; Methylcholanthrene; Neoplasm Transplantation; Rats; Sarcoma, Experimental; Time Factors
PubMed: 4759936
DOI: 10.1038/bjc.1973.149 -
Toxicological Sciences : An Official... Sep 2010The paper by Pansoy and coworkers investigates the effects of the aryl hydrocarbon receptor (AHR) ligand 3-methylcholanthrene (3MC) on recruitment of the AHR complex to...
The paper by Pansoy and coworkers investigates the effects of the aryl hydrocarbon receptor (AHR) ligand 3-methylcholanthrene (3MC) on recruitment of the AHR complex to human promoters in T47D breast cancer cells. The results are particularly important because they can be compared with a prior study using the potent AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the same cell line. The chromatin immunoprecipitation and promoter-focused microarrays (ChIP-chip) demonstrated that after treatment of T47D cells with 1microM 3MC, there were 241 AHR-3MC bound regions and many of these contained AHR-responsive elements. However, they also observed interactions with regions that do not contain these responsive elements, and subsequent analysis of selected target genes show that 3MC-dependent AHR binding did not necessarily predict Ah-responsiveness because induction, repression, and no effects were observed. A prior study with TCDD demonstrated that both 3MC and TCDD induced AHR binding to 127 common regions; however, there were significant differences in ligand (3MC vs. TCDD)-dependent AHR bound regions. The results illustrate the complexity of AHR signaling and also demonstrate that compared with TCDD as a reference ligand, 3MC is a selective AHR modulator.
Topics: Chromatin; Chromatin Immunoprecipitation; Humans; Methylcholanthrene; Promoter Regions, Genetic; Receptors, Aryl Hydrocarbon
PubMed: 20651249
DOI: 10.1093/toxsci/kfq193 -
The Biochemical Journal Oct 1982The interaction of substrates of the microsomal mixed-function oxidases with cytochromes P-450 and P-448 was investigated by using liver microsomes from rats pretreated...
The interaction of substrates of the microsomal mixed-function oxidases with cytochromes P-450 and P-448 was investigated by using liver microsomes from rats pretreated with phenobarbital or 3-methylcholanthrene, and with purified forms of the cytochromes isolated from rabbit liver. The two forms of the cytochrome have different substrate specificities; cytochrome P-450 has one type 1 substrate-binding site that can accommodate a large variety of substrates, but in contrast cytochrome P-448 may possess two type 1 substrate-binding sites, one of which is different to that of cytochrome P-450 in that it shows a specificity for substrates such as safrole and 9-hydroxy-ellipticine. These findings explain why the two forms of the cytochrome have different substrate specificities and play contrasting roles in the activation and deactivation of xenobiotics.
Topics: Animals; Benzphetamine; Binding Sites; Cytochrome P-450 CYP1A2; Cytochrome P-450 Enzyme System; Cytochromes; Ellipticines; Fluorenes; In Vitro Techniques; Male; Methylcholanthrene; Microsomes, Liver; Phenobarbital; Rats; Rats, Inbred Strains; Safrole; Spectrophotometry; Substrate Specificity
PubMed: 7181861
DOI: 10.1042/bj2070051 -
Toxicological Sciences : An Official... Sep 2010The aryl hydrocarbon receptor (AHR) is a ligand-activated protein that mediates the toxic actions of polycyclic aromatic and halogenated compounds. Identifying genes...
The aryl hydrocarbon receptor (AHR) is a ligand-activated protein that mediates the toxic actions of polycyclic aromatic and halogenated compounds. Identifying genes directly regulated by AHR is important in understanding the pathways regulated by this receptor. Here we used the techniques of chromatin immunoprecipitation and DNA microarrays (ChIP-chip) to detect AHR-bound genomic regions after 3-methylcholanthrene (3MC) treatment of T-47D human breast cancer cells. We identified 241 AHR-3MC-bound regions, and transcription factor-binding site analysis revealed a strong overrepresentation of the AHR-responsive element. Conventional ChIP confirmed recruitment of AHR to 26 regions with target gene responses to 3MC varying from activation to inhibition to having no effect. A comparison of identified AHR-3MC-bound regions with AHR-2,3,7,8-tetrchlorodibenzo-p-dioxin (TCDD)-bound regions from our previous study (Ahmed, S., Valen, E., Sandelin, A., and Matthews, J. (2009). Toxicol. Sci. 111, 254-266) revealed that 127 regions were common between the data sets. Time course ChIPs for six of the regions showed that 3MC induced gene-specific changes in histone H3 acetylation and methylation and induced differential oscillatory binding of AHR, with a periodicity between 1.5 and 2 h. Re-treatment of cells with 3MC failed to alter the oscillatory binding profiles of AHR or aryl hydrocarbon receptor nuclear translocator. Cells became responsive to 3MC but not TCDD after 24 h of exposure to 3MC, highlighting important differences in AHR responsiveness between the two ligands. Our results reveal a number of novel AHR-bound promoter regions and target genes that exhibit differential kinetic binding profiles and regulation by AHR.
Topics: Blotting, Western; Carcinogens; Chromatin Immunoprecipitation; Gene Expression; Humans; Methylcholanthrene; Oligonucleotide Array Sequence Analysis; Polychlorinated Dibenzodioxins; Receptors, Aryl Hydrocarbon
PubMed: 20348232
DOI: 10.1093/toxsci/kfq096 -
Proceedings of the National Academy of... May 2003There are large inter- and intraspecies differences in susceptibility to dioxin-induced toxicities. A critical question in risk assessment of dioxin and related...
There are large inter- and intraspecies differences in susceptibility to dioxin-induced toxicities. A critical question in risk assessment of dioxin and related compounds is whether humans are sensitive or resistant to their toxicities. The diverse responses of mammals to dioxin are strongly influenced by functional polymorphisms of the arylhydrocarbon receptor (AHR). To characterize responses mediated by the human AHR (hAHR), we generated a mouse possessing hAHR instead of mouse AHR. Responses of these mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3-methylcholanthrene were compared with the responses of naturally sensitive (C57BL6J) and resistant (DBA2) mice. Mice homozygous for hAHR exhibited weaker induction of AHR target genes such as cyp1a1 and cyp1a2 than did C57BL6J (Ahr(b-1/b-1)) mice. DBA2 (Ahr(d/d)) mice were less responsive to induction of cyp genes than C57BL6J mice. hAHR and DBA2 AHR exhibit similar ligand-binding affinities and homozygous hAHR and Ahr(d/d) mice displayed comparable induction of AHR target genes by 3-methylcholanthrene. However, when TCDD was administered, a greatly diminished response was observed in homozygous hAHR mice compared with Ahr(d/d) mice, indicating that hAHR expressed in mice is functionally less responsive to TCDD than DBA2 AHR. After maternal exposure to TCDD, homozygous hAHR fetuses developed embryonic hydronephrosis, but not cleft palate, whereas fetuses possessing Ahr(b-1) or Ahr(d) developed both anomalies. These results suggest that hAHR may define the specificity of the responses to various AHR ligands. Thus, the hAHR knock-in mouse is a humanized model mouse that may better predict the biological effects of bioaccumulative environmental toxicants like TCDD in humans.
Topics: Animals; Base Sequence; DNA Primers; Dioxins; Female; Humans; Kidney; Methylcholanthrene; Mice; Mice, Transgenic; Palate; Pregnancy; Prenatal Exposure Delayed Effects; RNA, Messenger; Receptors, Aryl Hydrocarbon; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 12730383
DOI: 10.1073/pnas.1037886100 -
Theoretical Biology & Medical Modelling Feb 2006The hypothesis of immunosurveillance suggests that new neoplasms arise very frequently, but most are destroyed almost at their inception by an immune response. Its... (Review)
Review
BACKGROUND
The hypothesis of immunosurveillance suggests that new neoplasms arise very frequently, but most are destroyed almost at their inception by an immune response. Its correctness has been debated for many years. In its support, it has been shown that the incidences of many tumor types, though apparently not all, tend to be increased in immunodeficient animals or humans, but this observation does not end the debate.
ALTERNATIVE MODEL
There is an alternative to the surveillance hypothesis; numerous studies have shown that the effect of an immune reaction on a tumor is biphasic. For each tumor, there is some quantitatively low level of immune reaction that, relative to no reaction, is facilitating, perhaps even necessary for the tumor's growth in vivo. The optimum level of this facilitating reaction may often be less than the level of immunity that the tumor might engender in a normal subject.
CONCLUSION
The failure of a tumor to grow as well in the normal as it does in the immunosuppressed host is probably not caused by a lack of tumor-cell killing in the suppressed host. Instead, the higher level of immune response in a normal animal, even if it does not rise to tumor-inhibitory levels, probably gives less positive support to tumor growth. This seems more than a semantic distinction.
Topics: Animals; Carcinogens; Female; Humans; Immunocompetence; Immunocompromised Host; Mammary Neoplasms, Experimental; Mammary Tumor Virus, Mouse; Methylcholanthrene; Mice; Mice, Nude; Mice, SCID; Models, Immunological; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Retroviridae Infections; Transplantation, Isogeneic; Tumor Virus Infections
PubMed: 16457723
DOI: 10.1186/1742-4682-3-6 -
The Journal of Toxicological Sciences Apr 2015The effects of the peroxisome proliferator, dehydroepiandrosterone sulfate (DHEAS), and the typical cytochrome P450 (CYP) inducers phenobarbital (PB) and...
The effects of the peroxisome proliferator, dehydroepiandrosterone sulfate (DHEAS), and the typical cytochrome P450 (CYP) inducers phenobarbital (PB) and 3-methylcholanthrene (3-MC) on fatty liver were examined in rats. Treating rats with orotic acid caused marked accumulation of lipid droplets in the liver. This effect of orotic acid was almost eradicated by co-treatment with DHEAS and PB. While DHEAS or PB alone also alleviated fatty liver, treatment with 3-MC caused little effect on a reduction in lipid droplets. Histopathological examinations revealed numerous peroxisomes in the liver of rats treated with DHEAS. In addition, a significant increase in the expression on hepatic CYPs was observed in rats the fatty liver of which was attenuated. Regarding other enzymes associated with hepatic fatty acid oxidation, the expression levels of sirtuin 1, sirtuin 6, and carnitine palmitoyltransferase 1 were also upregulated most markedly by treatment with DHEAS alone. Thus, the attenuation in fatty liver observed in the present study is likely due to peroxisome proliferation and the induction of fatty acid-metabolizing enzymes by DHEAS and typical CYP inducers.
Topics: Animals; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 Enzyme System; Dehydroepiandrosterone Sulfate; Drug Therapy, Combination; Fatty Acids; Fatty Liver; Liver; Male; Methylcholanthrene; Orotic Acid; Oxidation-Reduction; Peroxisomes; Phenobarbital; Rats, Sprague-Dawley; Sirtuin 1
PubMed: 25786523
DOI: 10.2131/jts.40.181 -
The Journal of Biological Chemistry Jun 1988In both primary cell cultures of rat hepatocytes and in liver, polycyclic aromatic hydrocarbons (PAHs) were found to influence the accumulation of the cytochrome P-450c...
In both primary cell cultures of rat hepatocytes and in liver, polycyclic aromatic hydrocarbons (PAHs) were found to influence the accumulation of the cytochrome P-450c and P-450d mRNAs by both transcriptional and post-transcriptional mechanisms. Following treatment with PAHs, cytochrome P-450c mRNA levels increased approximately 100-fold in both hepatocyte cultures and in liver, while transcription rates, measured by run-on transcription of isolated nuclei, increased 3-fold in hepatocyte cultures and 10-fold in liver. The difference in the -fold increases of mRNA level and transcription rate suggests that post-transcriptional, as well as transcriptional, mechanisms contributed to the regulation of cytochrome P-450c mRNA levels. Following treatment with PAHs, cytochrome P-450d mRNA levels increased 200-fold in hepatocyte cultures and 70-fold in liver, while transcription rates remained unchanged in hepatocyte cultures and increased only 1.7-fold in liver. This suggests that post-transcriptional mechanisms were of primary importance in regulating cytochrome P-450d mRNA levels. The newly developed hepatocyte primary cell culture system used in these studies differs from previously reported systems in that the cytochrome P-450d gene, as well as the cytochrome P-450c gene, were expressed in response to PAHs. In this cell culture system the regulation of these two genes was quite similar, although not identical, to that found in liver. The mechanisms controlling the tissue-specific expression of the genes encoding cytochromes P-450c and P-450d were also examined. The cytochrome P-450c mRNA was found in kidney, heart, and lung, as well as in liver, of PAH-treated rats, while the mature cytochrome P-450d mRNA was detected only in liver. The substantial increase in cytochrome P-450c mRNA in kidney in response to beta-napthoflavone was not associated with a detectable change in the transcription rate of cytochrome P-450c gene, indicating that cytochrome P-450c mRNA levels must be regulated primarily post-transcriptionally in kidney. Even though mature cytochrome P-450d mRNA could not be detected in kidney, the cytochrome P-450d gene was transcribed at a substantial rate in this tissue; therefore, the lack of accumulation of mature cytochrome P-450d mRNA in kidney must have been due to post-transcriptional control.
Topics: Animals; Benzoflavones; Cells, Cultured; Cytochrome P-450 Enzyme System; Genes; Kidney; Kinetics; Liver; Methylcholanthrene; Organ Specificity; Polychlorinated Dibenzodioxins; RNA Processing, Post-Transcriptional; RNA, Messenger; Rats; Transcription, Genetic; beta-Naphthoflavone
PubMed: 3379039
DOI: No ID Found