Induction of unscheduled DNA synthesis in hairless mouse epidermis by 8-methoxypsoralen plus ultraviolet A(PUVA).

Mori, Masaaki; Kobayashi, Hiroshi; Katsumura, Yoshio; Furihata, Chie

doi:10.2131/jts.26.1

Cited by 11 publications

(3 citation statements)

References 36 publications

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“…Genotoxicity testing Because S-59, like most psoralens, reversibly intercalates into DNA (the basis of the specificity of the PCT process), it was expected to be positive in certain in vitro mutagenicity assays. Another psoralen, 8-methoxypsoralen (8-MOP) has been tested in genotoxicity assays and was shown to induce unscheduled DNA synthesis in mouse epidermis 12 ; elicit genotoxicity in the micronucleus test in Chinese hamster V79 cells; 13 and induce photodamage, photogenotoxicity, repair, and gene induction in Saccharomyces cerevisiae. 14 Accordingly, S-59 was tested in standard in vitro and in vivo mutagenicity studies that complied with ICH guidelines for a novel pharmaceutical.…”

Section: Rationale For Toxicology Studiesmentioning

confidence: 99%

Pharmacokinetic and toxicology assessment of INTERCEPT (S-59 and UVA treated) platelets

Ciaravino¹,

McCullough

Dayan³

2001

Hum Exp Toxicol

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The pathogen inactivation process developed by Cerus and Baxter Healthcare Corporations uses the psoralen, S-59 (amotosalen) in an ex vivo photochemical treatment (PCT) process to inactivate viruses, bacteria, protozoans, and leukocytes in platelet concentrates and plasma. Studies were performed by intravenous infusion of S-59 PCT formulations-compound adsorption device (CAD) treatment and with non-UVA illuminated S-59, using doses that were multiples of potential clinical exposures. The studies comprised full pharmacokinetic, single and repeated-dose (up to 13 weeks duration) toxicity, safety pharmacology (CNS, renal, and cardiovascular), reproductive toxicity, genotoxicity, carcinogenicity testing in the p53- mouse, vein irritation, and phototoxicity. No specific target organ toxicity (clinical or histopathological), reproductive toxicity, or carcinogenicity was observed. S-59 and/or PCT formulations demonstrated CNS, ECG, and phototoxicity only at supraclinical doses. Based on the extremely large safety margins (>30,000 fold expected clinical exposures), the CNS and ECG observations are not considered to have any toxicological relevance. Additionally, after a complete assessment, mutagenicity and phototoxicity results are not considered relevant for the proposed use of INTERCEPT platelets. Thus, the results of an extensive series of in vitro and in vivo studies have not demonstrated any toxicologically relevant effects of platelet concentrates prepared by the INTERCEPT system.

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Section: Rationale For Toxicology Studiesmentioning

confidence: 99%

Pharmacokinetic and toxicology assessment of INTERCEPT (S-59 and UVA treated) platelets

Ciaravino¹,

McCullough

Dayan³

2001

Hum Exp Toxicol

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“…We studied the UDS method in the hairless mouse epidermis (89)(90)(91)(92). Five genotoxic skin carcinogens, benzo[a]pyrene, diepoxybutane, 7,12-dimethylbenzo[a]pyrene, MNNG, and 4NQO showed induction of UDS dose-dependently 2 h after treatment and a negative control, 1,2-epoxydodecane showed negative UDS (89).…”

Section: Attempts At Organ-speciˆc In Vivo Short-term Assays For the mentioning

confidence: 99%

Attempts at Organ-specific In Vivo Short-term Tests for Environmental Mutagens and Carcinogens in Rodent Liver and Stomach

Furihata

2013

Genes and Environment

Self Cite

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The primary motivation for conducting short-term tests for environmental mutagens and carcinogens has been to predict mutagens and/or carcinogens and to assess any associated risks. Organ-speciˆc in vivo short-term tests in rodents are valuable because chemical carcinogenesis is generally organ-speciˆc. I have attempted to develop various organ-speciˆc in vivo short-term tests mainly in rodent liver and stomach. Recently, our collaborative study group, Toxicogenomics/Japanese Environmental Mutagen Society･Mammalian Mutagenicity Study Group (JEMS･ MMS), attempted to use gene expression proˆling in in vivo short-term tests, conducted DNA microarrays to extract candidate marker genes, and later shifted to quantitative real-time PCR (qPCR) to proˆle the expression of selected genes. We successfully discriminated 8 genotoxic hepatocarcinogens from 4 non-genotoxic hepatocarcinogens by statistical analysis using principal component analysis (PCA) based on the gene expression proˆles for 12 genes (Aen, Bax, Btg2, Ccnf, Ccng1, Cdkn1a, Gdf15, Lrp1, Mbd1, Phlda3, Plk2, and Tubb2c) in mouse liver at 4 and 48 h following a single intraperitoneal administration of chemicals as determined by qPCR. More recently, we successfully performed a similar study in rat liver. Previously, my collaborators and I developed various organspeciˆc in vivo short-term test methods, including UDS (unscheduled DNA synthesis); RDS (replicative DNA synthesis) using a liquid scintillation counter in rat glandular stomach, forestomach, colon, and liver and hairless mouse epidermis; DNA single-strand scission (DSS); and ornithine decarboxylase assay (ODC) in rat glandular stomach on 62 compounds. Developing short-term tests that are helpful for the risk assessment of human mutagens and carcinogens would contribute to the development of ideal prediction methods.

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“…The widely used micronucle-us test (Igarashi, 2010), which detects small nuclei in a cell, can be performed in a variety of ways using human or rodent cells (as an in vitro assay) or living rodents (as an in vivo assay). The unscheduled DNA synthesis (UDS) test measures the DNA repair synthesis after dual incision and excision of oligonucleotides containing DNA lesions (Mori, 2001). Single cell gel electrophoresis (comet assay), which is a rapid, sensitive, and simple method, measures DNA damage at the level of individual cells (Recio, 2010).…”

Section: Introductionmentioning

confidence: 99%

A method for detecting genetic toxicity using the RNA synthesis response to DNA damage

2011

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-To date, biological risk assessment studies of chemicals that induce DNA lesions have been primarily based on the action of DNA polymerases during replication. However, DNA lesions interfere not only with replication but also with transcription. Therefore, detecting the damaging effects of DNA lesions during transcription might be important for estimating the safety of chemical mutagens and carcinogens. However, methods to address these effects have not been developed. Here, we report a simple, non-isotopic method for determining the toxicity of chemical agents by visualizing transcription in a mammalian cell system. The method is based on the measurement of the incorporation of bromouridine (as the uridine analogue) into the nascent RNA during RNA synthesis inhibition (RSI) induced by the stalling of RNA polymerases at DNA lesions on the transcribed DNA strand, which triggers transcriptioncoupled nucleotide excision repair (TC-NER). When we tested chemical agents (camptothecin, etoposide, 4-nitroquinoline-1-oxide, mitomycin C, methyl methanesulfonate, and cisplatin) in HeLa cells by the method, RSI indicative of genomic toxicity was observed in the nucleoli of the tested cells. This procedure provides the following advantages: 1) it uses common, affordable mammalian cells (HeLa cells, WI38VA13 cells, human dermal fibroblasts, or Chinese hamster ovary cells) rather than genetically modified microorganisms; 2) it can be completed within approximately 8 hr after the cells are prepared because RNA polymerase responses during TC-NER are faster than other DNA damage responses (replication, recombination, and apoptosis); and 3) it is safe because it uses non-radioactive bromouridine and antibodies to detect RNA synthesis on undamaged transcribed DNA strands.

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Induction of unscheduled DNA synthesis in hairless mouse epidermis by 8-methoxypsoralen plus ultraviolet A(PUVA).

Cited by 11 publications

References 36 publications

Pharmacokinetic and toxicology assessment of INTERCEPT (S-59 and UVA treated) platelets

Pharmacokinetic and toxicology assessment of INTERCEPT (S-59 and UVA treated) platelets

Attempts at Organ-specific In Vivo Short-term Tests for Environmental Mutagens and Carcinogens in Rodent Liver and Stomach

A method for detecting genetic toxicity using the RNA synthesis response to DNA damage

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