Regulation of 2‐acetylaminofluorene‐and 3‐methylcholanthrene‐mediated induction of multidrug resistance and cytochrome P450IA gene family expression in primary hepatocyte cultures and rat liver

Gant, Timothy W.; Silverman, Jeffrey A.; Bisgaard, Hanne Cathrine; Burt, Richard K.; Mariño, P; Thorgeirsson, Snorri S.

doi:10.1002/mc.2940040614

Cited by 123 publications

(81 citation statements)

References 57 publications

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“…Previously we and others have demonstrated that several xenobiotics are able to induce the mdr gene expression (33,36,37,42). One of the mnost potent mdr inducers in the rat is 2-acetylaminofluorene (2-AAF).…”

Section: Resultsmentioning

confidence: 93%

“…One of the mnost potent mdr inducers in the rat is 2-acetylaminofluorene (2-AAF). In rat liver and isolated hepatocytes, AAF is able to induce transcription of the mndrl genes and thus elevate their expression measured at both the mRNA and protein levels (37). In monkeys AAF is also able to induce mdr expression though the effect is less and more variable than that seen in the rat (Gant et al, unpublished data).…”

Section: Resultsmentioning

confidence: 97%

“…Hepatocytes isolated from rats previously exposed to acetylaminofluorene (AAF) display an increased resistance to several cytotoxic drugs including actinomycin D (35). Expression of the mdr gene family can be induced in rat liver following acute exposure to several xenobiotics (36,37).…”

Section: Introductionmentioning

confidence: 99%

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Requirement for Metabolic Activation of Acetylaminofluorene to Induce Multidrug Gene Expression

Gant¹,

Schrenk²,

Silverman³

et al. 1994

Environmental Health Perspectives

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Previously we have demonstrated that several xenobiotics can induce multidrug (mdr) gene expression in cultures of primary isolated hepatocytes.One of the best of these xenobiotic inducers in rat hepatocytes is 2-acetylaminofluorene (2-AAF), which induces mdr expression by an enhancement of mdr gene transcription. In all species studied to date, AAF is extensively and variously metabolized. In this study we have sought to determine if AAF per se or a metabolite is responsible for mediating the increase in mdr gene transcription and expression. This study demonstrates that AAF per se is not active, but that the effect of AAF we have observed on mdr gene transcription and expression in the rat is due to the formation of a reactive metabolite(s). Our data indicate that this reactive metabolite is probably N-acetoxy-2-aminofluorene or the sulfate ester of N-hydroxy-AAF. The requirement for the formation of one of these metabolites may explain the differences in species response to AAF, in terms of mdr gene expression, that we have observed. We hypothesize that the mechanism by which mdr gene transcription is increased in response to AAF involves a covalent interaction between a reactive metabolite and an mdr gene regulatory protein. Our current work is concerned with the exploration of this hypothesis. -Environ Health Perspect 102(Suppl 6): 209-212 (1994)

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Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 97%

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Requirement for Metabolic Activation of Acetylaminofluorene to Induce Multidrug Gene Expression

Gant¹,

Schrenk²,

Silverman³

et al. 1994

Environmental Health Perspectives

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“…For example the nuclear run on assay has been used to show that transcription of the ABCB1 gene can be increased after chemical exposure in the liver [28]. It should be possible to undertake such an analysis on a global scale using a microarray.…”

Section: Array Comparative Genome Hybridisation (Arraycgh)mentioning

confidence: 99%

Novel and future applications of microarrays in toxicological research

Gant

2007

Expert Opin. Drug Metab. Toxicol.

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Abstract.Microarray technologies have both fascinated and frustrated the toxicological community since their introduction about a decade ago. Fascination arose from the possibility offered by the technology to gain a profound incite into the cellular response to chemically mediated stress, and the potential that this genomic signature would be indicative of the biological mechanism by which that stress was induced.Frustrations have arisen primarily from technical factors such as data variance, the requirement for the application of advanced statistical and mathematical analysis and difficulties associated with actually recognising signature gene expression patterns, and discerning mechanisms. Toxicogenomics was predicted to make toxicological assessment and extrapolation easier, faster and cheaper. The reality has been that toxicogenomics is difficult. However, its potential when properly applied has been indicated by some well designed toxicogenomics studies, particularly in the differentiation of genotoxins from non-genotoxins. Technology waits though for no man. While the toxicological community has been working to apply transcriptomics (mRNA levels) in toxicology the technology has moved beyond this application into new arenas. Some have application to toxicology and are reviewed here, except transcriptomics which has been extensively written about before. Discussed are the application of microarray technologies applied to the genome per se (amplifications, deletions, epigenetic change), mRNA translation and its control mechanisms through miRNA. Which of the new genomics technologies will find most application in toxicology? In the opinion of this author there are three potentially major applications; 1) ArrayCGH in assessment and recognition of genotoxicity, 2) epigenetic assessment in developmental and transgenerational toxicology and, 3) miRNA assessment in all toxicology types but in particular developmental toxicology.

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“…Double immunofluorescence microscopy with the carcinogens, as well as mechanically and chemically induced keratin polyclonal antibody and the mab C219 at this cholestasis, have been previously shown to induce the exprestime point revealed a complete loss of Pgp staining in sion of mdr genes and their products, Pgp, in rodent and affected cells, although remaining hepatocytes with un-nonhuman primate liver. [15][16][17][18][19][20][21] Pgp is often overexpressed in altered KIF meshwork showed a strong reaction with tumor cells exhibiting resistance to the cytotoxic effects of a the C219 antibody. Northern blot analyses revealed a number of structurally and functionally unrelated drugs.…”

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confidence: 99%

Experimental Mallory body formation is accompanied by modulation of the expression of multidrug-resistance genes and their products

Stumptner

Riegelnegg

et al. 1996

Hepatology

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treatment with griseofulvin (GF) or 3,5-diethoxycarbonylMallory bodies (MBs) are characteristic morphological 1,4-dihydrocollidine (DDC). 2,3 Morphological, immunological, features of alcoholic hepatitis and are also found in and biochemical characterization revealed that keratins, other chronic liver disorders and hepatocellular neohigh-molecular-weight and poorly soluble non-keratin complasms. MBs can be produced in mouse liver by chronic ponents, and tau-like proteins are major constituents of administration of the porphyrinogenic drugs griseofulMBs. [4][5][6][7][8][9] It has also been shown that transglutaminase-invin (GF) and 3,5-diethoxy-carbonyl-1,4-dihydrocollidine duced glutamyl-lysine crosslinks and ubiquitin are involved (DDC). The mechanisms causing the formation of MBs in MB formation. [10][11][12] Moreover, immunofluorescence microsare poorly understood, and the significance of MB forcopy revealed that formation of MBs is accompanied by demation during the course of liver disease remains unrangement and even loss of the keratin intermediate filament clear. We investigated the relationship between the mechanisms underlying the formation of MBs and the (KIF) cytoskeleton in hepatocytes. 6,8,13 MB-containing heparegulation of multidrug resistance (mdr) genes and their tocytes seem to be viable, and no fundamental differences in products, the P-glycoproteins (Pgp). Immunofluores-the metabolic functions between these cells and morphologicence microscopy using the monoclonal antibody C219 cally normal-appearing hepatocytes have been demonrevealed an increase of Pgp expression in almost all he-strated, at least on the basis of histochemical staining for patocytes after 3 to 8 days of feeding mice DDC-and GF-several key enzymes. 13,14 The mechanisms of MB formation containing diets. However, after approximately 4 weeks are poorly understood, and the significance of MB-containing of DDC and approximately 8 weeks of GF feeding, when cells in many chronic liver diseases remains a mystery. the first small MBs appeared and loosening and diminuTo further define the mechanisms of MB formation and to tion of keratin intermediate filament (KIF) cytoskeleton detect functional differences between morphologically altered occurred in some hepatocytes, a decrease or loss of Pgp and normal hepatocytes, we investigated whether the prodstaining in affected hepatocytes was observed. After ucts of the multidrug resistance (mdr) genes, P-glycoproteins feeding mice DDC for 6 weeks and GF for 12 weeks, many (Pgp), are altered in DDC-and GF-treated mouse livers in hepatocytes contained MBs and displayed a disruption relation to the formation of MBs. The decision to choose the of the immunohistochemically demonstrable KIF mesh-Pgp was prompted by the fact that several xenobiotics and work. Double immunofluorescence microscopy with the carcinogens, as well as mechanically and chemically induced keratin polyclonal antibody and the mab C219 at this cholestasis, have been previously shown to induce the exprestime point revealed a com...

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Regulation of 2‐acetylaminofluorene‐and 3‐methylcholanthrene‐mediated induction of multidrug resistance and cytochrome P450IA gene family expression in primary hepatocyte cultures and rat liver

Cited by 123 publications

References 57 publications

Requirement for Metabolic Activation of Acetylaminofluorene to Induce Multidrug Gene Expression

Requirement for Metabolic Activation of Acetylaminofluorene to Induce Multidrug Gene Expression

Novel and future applications of microarrays in toxicological research

Experimental Mallory body formation is accompanied by modulation of the expression of multidrug-resistance genes and their products

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