scholarly journals Establishment of Novel Genotoxicity Assay System Using Murine Normal Epithelial Tissue-Derived Organoids

2021 ◽  
Vol 12 ◽  
Author(s):  
Masami Komiya ◽  
Rikako Ishigamori ◽  
Mie Naruse ◽  
Masako Ochiai ◽  
Noriyuki Miyoshi ◽  
...  
Keyword(s):  
Safety Assessment ◽  
General Procedure ◽  
Metabolic Activation ◽  
Chemical Carcinogenesis ◽  
Dna Adduct ◽  
Organ Specificity ◽  
Epithelial Tissue ◽  
Target Tissue ◽  
Middle Term

Short-/middle-term and simple prediction studies for carcinogenesis are needed for the safety assessment of chemical substances. To establish a novel genotoxicity assay with an in vivo mimicking system, we prepared murine colonic/pulmonary organoids from gpt delta mice according to the general procedure using collagenase/dispase and cultured them in a 3D environment. When the organoids were exposed to foodborne carcinogens—2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) and acrylamide (AA)—in the presence of metabolic activation systems, mutation frequencies (MFs) occurring in the gpt gene dose-dependently increased. Moreover, the mutation spectrum analysis indicated predominant G:C to T:A transversion with PhIP, and A:T to C:G and A:T to T:A transversion with AA. These data correspond to those of a previous study describing in vivo mutagenicity in gpt delta mice. However, organoids derived from the liver, a non-target tissue of PhIP-carcinogenesis, also demonstrated genotoxicity with a potency comparable to colonic organoids. Organoids and PhIP were directly incubated in the presence of metabolic activation systems; therefore, there was a lack of organ specificity, as observed in vivo. Additionally, PhIP-DNA adduct levels were comparable in hepatic and colonic organoids after PhIP exposure. Taken together, the organoids prepared in the present study may be helpful to predict chemical carcinogenesis.

Metabolic activation of the tumorigenic pyrrolizidine alkaloid, monocrotaline, leading to DNA adduct formation in vivo

2005 ◽  
Vol 226 (1) ◽  
pp. 27-35 ◽  
Author(s):  
Yu-Ping Wang ◽  
Jian Yan ◽  
Richard D. Beger ◽  
Peter P. Fu ◽  
Ming W. Chou
Keyword(s):  
Pyrrolizidine Alkaloid ◽  
Metabolic Activation ◽  
Adduct Formation ◽  
Dna Adduct

scholarly journals Genes and enzymes of metabolic activation of xenobiotics in chemical carcinogenesis

2003 ◽  
Vol 1 (1) ◽  
pp. 30-35
Author(s):  
Veniamin V Khudolei
Keyword(s):  
Genetic Polymorphism ◽  
Metabolic Activation ◽  
Chemical Carcinogenesis ◽  
Organ Specificity ◽  
Gene Products ◽  
Initial Stage ◽  
Carcinogenic Substances ◽  
Primary Key ◽  
Microsomal Hydroxylation

In the initial stage of chemical carcinogenesis the primary key event is metabolic activation of exogenic carcinogenic substances. The main enzymes of carcinogen's biotransformation (microsomal hydroxylation, reactions of conjugation) and genes which controlling the activity of these enzymes, has been characterized. The tissue(organ)specificity of expression of gene products (isoforms of su-perfamilies of CYPs and GSTs, family of NATs) as well as genetic polymorphism of enzymes involving into the biotransformation of carcinogenic xenobiotics were demonstrated

Metabolic Activation of the Tumorigenic Pyrrolizidine Alkaloid, Riddelliine, Leading to DNA Adduct Formation in Vivo

2001 ◽  
Vol 14 (1) ◽  
pp. 101-109 ◽  
Author(s):  
Ya-Chen Yang ◽  
Jian Yan ◽  
Daniel R. Doerge ◽  
Po-Cheun Chan ◽  
Peter P. Fu ◽  
...  
Keyword(s):  
Pyrrolizidine Alkaloid ◽  
Metabolic Activation ◽  
Adduct Formation ◽  
Dna Adduct

scholarly journals Ellipticine and benzo(a)pyrene increase their own metabolic activation via modulation of expression and enzymatic activity of cytochromes P450 1A1 and 1A2

2008 ◽  
Vol 1 (2) ◽  
pp. 160-168 ◽  
Author(s):  
Dagmar Aimová ◽  
Jitka Poljaková ◽  
Věra Kotrbová ◽  
Michaela Moserová ◽  
Eva Frei ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Dna Adducts ◽  
Cytochromes P450 ◽  
Antineoplastic Agent ◽  
Metabolic Activation ◽  
Experimental Models ◽  
Adduct Formation ◽  
Dna Adduct

Ellipticine and benzo(a)pyrene increase their own metabolic activation via modulation of expression and enzymatic activity of cytochromes P450 1A1 and 1A2Two compounds known to covalently bind to DNA after their activation with cytochromes P450 (CYPs), carcinogenic benzo(a)pyrene (BaP) and an antineoplastic agent ellipticine, were investigated for their potential to induce CYP and NADPH:CYP reductase (POR) enzymes in rodent livers, the main target organ for DNA adduct formation. Two animal models were used in the study: (i) rats as animals mimicking the fate of ellipticine in humans and (ii) mice, especially wild-type (WT) and hepatic POR null (HRN™) mouse lines. Ellipticine and BaP induce expression of CYP1A enzymes in livers of experimental models, which leads to increase in their enzymatic activity. In addition, both compounds are capable of generating DNA adducts, predominantly in livers of studied organisms. As determined by32P postlabelling analysis, levels of ellipticine-derived DNA adducts formedin vivoin the livers of HRN™ mice were reduced (by up to 65%) relative to levels in WT mice, indicating that POR mediated CYP enzyme activity is important for the activation of ellipticine. In contrast to these results, 6.4 fold higher DNA binding of BaP was observed in the livers of HRN™ mice than in WT mice. This finding suggests a detoxication role of CYP1A in BaP metabolismin vivo. Inin vitroexperiments, DNA adduct formation in calf thymus DNA was up to 25 fold higher in incubations of ellipticine or BaP with microsomes from pretreated animals than with controls. This stimulation effect was attributed to induction of CYP1A1/2 enzymes, which are responsible for oxidative activation of both compounds to the metabolites generating major DNA adductsin vitro. Taken together, these results demonstrate that by inducing CYP1A1/2, ellipticine and BaP modulate their own enzymatic metabolic activation and detoxication, thereby modulating their either pharmacological (ellipticine) and/or genotoxic potential (both compounds).

Ultrasound-based Safety Assessment during Moving Organ Tracking Towards In Vivo Focused Ultrasound Therapy

2019 ◽  
Author(s):  
A Mariani ◽  
◽  
L Morchi ◽  
A Diodato ◽  
A Cafarelli ◽  
...  
Keyword(s):  
Safety Assessment ◽  
Focused Ultrasound ◽  
Ultrasound Therapy

scholarly journals Targeting the Extracellular Matrix in Abdominal Aortic Aneurysms Using Molecular Imaging Insights

2021 ◽  
Vol 22 (5) ◽  
pp. 2685
Author(s):  
Lisa Adams ◽  
Julia Brangsch ◽  
Bernd Hamm ◽  
Marcus R. Makowski ◽  
Sarah Keller
Keyword(s):  
Extracellular Matrix ◽  
Molecular Imaging ◽  
Molecular Targets ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Type I ◽  
Target Tissue ◽  
Pharmacologic Treatment ◽  
Abdominal Aortic

This review outlines recent preclinical and clinical advances in molecular imaging of abdominal aortic aneurysms (AAA) with a focus on molecular magnetic resonance imaging (MRI) of the extracellular matrix (ECM). In addition, developments in pharmacologic treatment of AAA targeting the ECM will be discussed and results from animal studies will be contrasted with clinical trials. Abdominal aortic aneurysm (AAA) is an often fatal disease without non-invasive pharmacologic treatment options. The ECM, with collagen type I and elastin as major components, is the key structural component of the aortic wall and is recognized as a target tissue for both initiation and the progression of AAA. Molecular imaging allows in vivo measurement and characterization of biological processes at the cellular and molecular level and sets forth to visualize molecular abnormalities at an early stage of disease, facilitating novel diagnostic and therapeutic pathways. By providing surrogate criteria for the in vivo evaluation of the effects of pharmacological therapies, molecular imaging techniques targeting the ECM can facilitate pharmacological drug development. In addition, molecular targets can also be used in theranostic approaches that have the potential for timely diagnosis and concurrent medical therapy. Recent successes in preclinical studies suggest future opportunities for clinical translation. However, further clinical studies are needed to validate the most promising molecular targets for human application.

THE INFLUENCE OF SERUM ON THE UPTAKE, CONVERSION AND ACTION OF DIHYDROTESTOSTERONE IN RAT PROSTATE GLANDS IN ORGAN CULTURE

1975 ◽  
Vol 64 (2) ◽  
pp. 289-297 ◽  
Author(s):  
ILSE LASNITZKI ◽  
HILARY R. FRANKLIN
Keyword(s):  
Organ Culture ◽  
Horse Serum ◽  
Target Tissue ◽  
Serum Free Medium ◽  
Free Medium ◽  
Serum Free ◽  
Human Pregnancy ◽  
Human Male ◽  
Columnar Cells

SUMMARY The influence of serum on the uptake, conversion and action of dihydrotestosterone in relation to the sex steroid binding protein, TeBG, has been investigated in rat ventral prostates in organ culture. The organs were incubated with [1,2-3H]dihydrotestosterone in: (1) serum-free medium, (2) horse serum, foetal and newborn bovine serum or (3) human male and human pregnancy serum. With all sera the uptake of dihydrotestosterone fell with rising serum concentration, at first steeply and then more gradually. At the same concentration, the uptake was significantly lower in explants incubated with human pregnancy serum than in those kept with human male serum. The conversion of dihydrotestosterone to androstanediol followed the same pattern and less androstanediol was formed in the presence of pregnancy serum. Since pregnancy serum contains higher amounts of TeBG than male serum, the lowered uptake suggests that only the free hormone was available to the target organ. Addition of unlabelled dihydrotestosterone resulted in a higher uptake than that measured in explants incubated with the labelled steroid only. The effect of the human sera on uptake and conversion was correlated with the androgenic activity of dihydrotestosterone applied at physiological concentrations and expressed as the percentage of secretory columnar cells present. The degree of maintenance closely corresponded to the uptake of the hormone. In serum-free medium, the number of columnar cells approached the values found in vivo, with male serum their number, though reduced, was still substantial, with pregnancy serum it was extremely low. It is concluded that the amounts of TeBG present in serum regulate the supply of the hormone to the target tissue and thus control its biological action.

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