Repeated-dose liver and gastrointestinal tract micronucleus assays for quinoline in rats

Uno, Fuyumi; Tanaka, Jin; Ueda, Maya; Nagai, Miho; Fukumuro, Masahito; Natsume, Masakatsu; Oba, Michiyo; Akahori, Ayaka; Masumori, Shoji; Takami, Shigeaki; Wako, Yumi; Kawasako, Kazufumi; Kougo, Y; Ohyama, Wakako; Narumi, Kazunori; Fujiishi, Yohei; Okada, Emiko; Hayashi, Makoto

doi:10.1016/j.mrgentox.2015.01.003

Cited by 8 publications

(8 citation statements)

References 19 publications

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“…While DEN and QUIN did not induce micronuclei in hematopoietic cells, they were observed to induce MNHEP in two different study designs, and similar results were generated by conventional microscopy and a novel flow cytometric method. This tissue specificity agrees with reports by the JEMS/MMS group (Hamada et al, ; Uno et al, ), and the current data also supports their conclusion that there are some advantages to using a protracted dosing schedule when studying rats that are 6 weeks of age at time of treatment. That being said, clear induction of MNHEP using an acute treatment schedule were observed, and short‐term experimental designs may have utility when training laboratory personnel on aspects of MNHEP enumeration, as well as for hazard identification, so long as animals' age is chosen carefully with respect to the proportion of dividing cells.…”

Section: Resultssupporting

confidence: 93%

“…The absence of remarkable changes to these biomarkers, in light of increases to normalized liver weight, is suggestive of hypertrophy. This interpretation is supported by histological observations reported by Uno and colleagues in the Japanese JEMS/MMS group's QUIN study (Uno et al, 2015b).…”

Section: Quin: 3-day Studysupporting

confidence: 76%

“…Most recently this body of work focused on a repeat‐treatment rat liver micronucleus assay, and promising results were obtained for 6‐week old rats exposed to test articles over 14 or 28 consecutive days. This important research was summarized in several publications, including an IWGT report (Uno et al, ), as well as papers published by the JEMS/MMS group (Hamada et al, ; Uno et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…The present report describes a novel flow cytometric method that complements work being done in this area by addressing certain disadvantages with microscopy‐based MNHEP scoring practices, especially in terms of throughput capacity and objectivity, with the further advantage of providing information about hepatocyte proliferation. The proof‐of‐principle studies described herein were conducted with diethylnitrosamine (DEN) and quinoline (QUIN), two chemicals that are reportedly negative in the MN‐RET assay, but capable of inducing MNHEP (Hamada et al, ; Uno et al, ). Thus, while many hepatocarcinogens that require enzymatic bioactivation in order to form proximate genotoxic and tumorigenic metabolites are positive in the MN‐RET assay, DEN and QUIN highlight the desirability of investigating hepatocytes in addition to hematopoietic cells, as some metabolites' high reactivity and short half‐life lead to tissue‐specific responses (Reigh et al, ; Kang et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Flow cytometric method for scoring rat liver micronuclei with simultaneous assessments of hepatocyte proliferation

Avlasevich

Khanal

Singh

et al. 2018

Environ and Mol Mutagen

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The current report describes a newly devised method for automatically scoring the incidence of rat hepatocyte micronuclei (MNHEP) via flow cytometry, with concurrent assessments of hepatocyte proliferation-frequency of Ki-67-positive nuclei, and the proportion of polyploid nuclei. Proof-of-concept data are provided from experiments performed with 6-week old male Crl:CD(SD) rats exposed to diethylnitrosamine (DEN) or quinoline (QUIN) for 3 or 14 consecutive days. Non-perfused liver tissue was collected 4 days after cessation of treatment in the case of 3-day studies, or 1 day after last administration in the case of 14-day studies for processing and flow cytometric analysis. In addition to livers, blood samples were collected one day after final treatment for micronucleated reticulocyte (MN-RET) measurements. Dose-dependent increases in MNHEP, Ki-67-positive nuclei, and polyploidy were observed in 3- and 14-day DEN studies. Both treatment schedules resulted in elevated %MNHEP for QUIN-exposed rats, and while cell proliferation effects were subtle, appreciable increases to normalized liver weights were observed. Whereas DEN caused markedly higher %MNHEP when exposure was extended to two weeks, QUIN-induced MNHEP were slightly increased with protracted dosing. Parallel microscopy-based MNHEP frequencies were highly correlated with flow cytometry-based measurements (four study/aggregate R = 0.80). No increases in MN-RET were seen in any of the four studies. Collectively, these results suggest liver micronuclei are amenable to an automated scoring technique that provides objective analyses and higher information content relative to conventional microscopy. Additional work is needed to expand the number and types of chemicals tested, identify the most advantageous treatment schedules, and test the transferability of the method. Environ. Mol. Mutagen. 59:176-187, 2018. © 2018 Wiley Periodicals, Inc.

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Section: Resultssupporting

confidence: 93%

Section: Quin: 3-day Studysupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Flow cytometric method for scoring rat liver micronuclei with simultaneous assessments of hepatocyte proliferation

Avlasevich

Khanal

Singh

et al. 2018

Environ and Mol Mutagen

View full text Add to dashboard Cite

show abstract

“…Quinoline also induces chromosomal aberration and sister chromatid exchange in rat hepatocytes after oral administration (Asakura et al, 1997). In a recent in vivo study, oral administration of quinoline induced an increase in the frequency of micronucleated hepatocytes (Uno et al, 2015). Thus the genotoxicity of quinoline is supported by a number of genotoxicity assays (in vitro and in vivo).…”

Section: Discussionmentioning

confidence: 95%

Carcinogenicity of quinoline by drinking-water administration in rats and mice

Matsumoto¹,

Kano²,

Suzuki³

et al. 2018

J. Toxicol. Sci.

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-The carcinogenicity of quinoline was examined by administrating quinoline in the drinking water to groups of 50 F344/DuCrj rats and 50 Crj: BDF1 mice of each sex. In rats, the doses of quinoline were 0, 200, 400, and 800 ppm for males and 0, 150, 300, and 600 ppm for females. In male rats, administration of quinoline was terminated at week 96 due to high mortality caused by tumors. There were significant increases of hepatocellular adenomas, hepatocellular carcinomas, hepatocellular adenomas and/or carcinomas (combined), and liver hemangiomas, hemangiosarcomas, hemangiomas and/ or hemangiosarcomas (combined) in both male and female rats, and nasal esthesioneuroepitheliomas and sarcoma NOS (not otherwise specified) in males. In mice, doses of quinoline were 0, 150, 300 and 600 ppm for both males and females. Administration of quinoline was terminated at week 65 in males and at week 50 in females due to high mortality caused by tumors. There were marked increases of hemangiomas, hemangiosarcomas, and hemangiomas and/or hemangiosarcomas (combined) in the retroperitoneum, mesenterium, and liver in males, and in the retroperitoneum, mesenterium, peritoneum, and subcutis in females. Additionally, histiocytic sarcomas were statistically increased in the livers of female mice. Thus the present studies provided clear evidence of carcinogenic activity of quinoline administered in the drinking water in both rats and mice.

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Quinolines derivatives as promising new antifungal candidates for the treatment of candidiasis and dermatophytosis

et al. 2020

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Fungal infections have emerged as a current serious global public health problem. The main problem involving these infections is the expansion of multidrug resistance. Therefore, the prospection of new compounds with efficacy antifungal becomes necessary. Thus, this study evaluated the antifungal profile and toxicological parameters of quinolines derivatives against Candida spp. and dermatophyte strains. As a result, a selective anti-dermatophytic action was demonstrated by compound 5 (geometric means (GM = 19.14 μg ml −1 )). However, compounds 2 (GM = 50 μg ml −1 ) and 3 (GM = 47.19 μg ml −1 ) have presented only anti- Candida action. Compounds 3 and 5 did not present cytotoxic action. Compound 5 did not produce dermal and mucosal toxicity. In addition, this compound showed the absence of genotoxic potential, suggesting safety for topical and systemic use. Quinolines demonstrated a potent anti-dermatophytic and anti-yeast action. Moreover, compound 5 presented an excellent toxicological profile, acting as a strong candidate for the development of a new effective and safe compound against dermatophytosis of difficult treatment. Electronic supplementary material The online version of this article (10.1007/s42770-020-00348-4) contains supplementary material, which is available to authorized users.

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Repeated-dose liver and gastrointestinal tract micronucleus assays for quinoline in rats

Cited by 8 publications

References 19 publications

Flow cytometric method for scoring rat liver micronuclei with simultaneous assessments of hepatocyte proliferation

Flow cytometric method for scoring rat liver micronuclei with simultaneous assessments of hepatocyte proliferation

Carcinogenicity of quinoline by drinking-water administration in rats and mice

Quinolines derivatives as promising new antifungal candidates for the treatment of candidiasis and dermatophytosis

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