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Safrole-2′,3′-oxide induces cytotoxic and genotoxic effects in HepG2 cells and in mice

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Title: Safrole-2′,3′-oxide induces cytotoxic and genotoxic effects in HepG2 cells and in mice
Authors: Chiang, Su-yin1 sychiang@mail.cmu.edu.tw, Lee, Pei-yi1, Lai, Ming-tsung2,3, Shen, Li-ching4, Chung, Wen-sheng4, Huang, Hui-fen1, Wu, Kuen-yuh5, Wu, Hsiu-ching6
Source: Mutation Research - Genetic Toxicology & Environmental Mutagenesis. Dec2011, Vol. 726 Issue 2, p234-241. 8p.
Subject Terms: *Genetic toxicology, *Cell-mediated cytotoxicity, Sassafras, Electrophiles, Antineoplastic agents, Plant metabolites, Liver cells, Liver tumors, Cytokinesis
Abstract: Abstract: Safrole-2′,3′-oxide (SAFO) is a reactive electrophilic metabolite of the hepatocarcinogen safrole, the main component of sassafras oil. Safrole occurs naturally in a variety of spices and herbs, including the commonly used Chinese medicine Xi xin (Asari Radix et Rhizoma) and Dong quai (Angelica sinensis). SAFO is the most mutagenic metabolite of safrole tested in the Ames test. However, little or no data are available on the genotoxicity of SAFO in mammalian systems. In this study, we investigated the cytotoxicity and genotoxicity of SAFO in human HepG2 cells and male FVB mice. Using MTT assay, SAFO exhibited a dose- and time-dependent cytotoxic effect in HepG2 cells with TC50 values of 361.9μM and 193.2μM after 24 and 48h exposure, respectively. In addition, treatment with SAFO at doses of 125μM and higher for 24h in HepG2 cells resulted in a 5.1–79.6-fold increase in mean Comet tail moment by the alkaline Comet assay and a 2.6–7.8-fold increase in the frequency of micronucleated binucleated cells by the cytokinesis-block micronucleus assay. Furthermore, repeated intraperitoneal administration of SAFO (15, 30, 45, and 60mg/kg) to mice every other day for a total of twelve doses caused a significant dose-dependent increase in mean Comet tail moment in peripheral blood leukocytes (13.3–43.4-fold) and in the frequency of micronucleated reticulocytes (1.5–5.8-fold). Repeated administration of SAFO (60mg/kg) to mice caused liver lesions manifested as a rim of ballooning degeneration of hepatocytes immediately surrounding the central vein. Our data clearly demonstrate that SAFO significantly induced cytotoxicity, DNA strand breaks, micronuclei formation both in human cells in vitro and in mice. More studies are needed to explore the role SAFO plays in safrole-induced genotoxicity. [Copyright &y& Elsevier]
Copyright of Mutation Research - Genetic Toxicology & Environmental Mutagenesis is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Safrole-2′,3′-oxide induces cytotoxic and genotoxic effects in HepG2 cells and in mice
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  Data: <searchLink fieldCode="AR" term="%22Chiang%2C+Su-yin%22">Chiang, Su-yin</searchLink><relatesTo>1</relatesTo><i> sychiang@mail.cmu.edu.tw</i><br /><searchLink fieldCode="AR" term="%22Lee%2C+Pei-yi%22">Lee, Pei-yi</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Lai%2C+Ming-tsung%22">Lai, Ming-tsung</searchLink><relatesTo>2,3</relatesTo><br /><searchLink fieldCode="AR" term="%22Shen%2C+Li-ching%22">Shen, Li-ching</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Chung%2C+Wen-sheng%22">Chung, Wen-sheng</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Huang%2C+Hui-fen%22">Huang, Hui-fen</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Wu%2C+Kuen-yuh%22">Wu, Kuen-yuh</searchLink><relatesTo>5</relatesTo><br /><searchLink fieldCode="AR" term="%22Wu%2C+Hsiu-ching%22">Wu, Hsiu-ching</searchLink><relatesTo>6</relatesTo>
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  Data: <searchLink fieldCode="JN" term="%22Mutation+Research+-+Genetic+Toxicology+%26+Environmental+Mutagenesis%22">Mutation Research - Genetic Toxicology & Environmental Mutagenesis</searchLink>. Dec2011, Vol. 726 Issue 2, p234-241. 8p.
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  Data: *<searchLink fieldCode="DE" term="%22Genetic+toxicology%22">Genetic toxicology</searchLink><br />*<searchLink fieldCode="DE" term="%22Cell-mediated+cytotoxicity%22">Cell-mediated cytotoxicity</searchLink><br /><searchLink fieldCode="DE" term="%22Sassafras%22">Sassafras</searchLink><br /><searchLink fieldCode="DE" term="%22Electrophiles%22">Electrophiles</searchLink><br /><searchLink fieldCode="DE" term="%22Antineoplastic+agents%22">Antineoplastic agents</searchLink><br /><searchLink fieldCode="DE" term="%22Plant+metabolites%22">Plant metabolites</searchLink><br /><searchLink fieldCode="DE" term="%22Liver+cells%22">Liver cells</searchLink><br /><searchLink fieldCode="DE" term="%22Liver+tumors%22">Liver tumors</searchLink><br /><searchLink fieldCode="DE" term="%22Cytokinesis%22">Cytokinesis</searchLink>
– Name: Abstract
  Label: Abstract
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  Data: Abstract: Safrole-2′,3′-oxide (SAFO) is a reactive electrophilic metabolite of the hepatocarcinogen safrole, the main component of sassafras oil. Safrole occurs naturally in a variety of spices and herbs, including the commonly used Chinese medicine Xi xin (Asari Radix et Rhizoma) and Dong quai (Angelica sinensis). SAFO is the most mutagenic metabolite of safrole tested in the Ames test. However, little or no data are available on the genotoxicity of SAFO in mammalian systems. In this study, we investigated the cytotoxicity and genotoxicity of SAFO in human HepG2 cells and male FVB mice. Using MTT assay, SAFO exhibited a dose- and time-dependent cytotoxic effect in HepG2 cells with TC50 values of 361.9μM and 193.2μM after 24 and 48h exposure, respectively. In addition, treatment with SAFO at doses of 125μM and higher for 24h in HepG2 cells resulted in a 5.1–79.6-fold increase in mean Comet tail moment by the alkaline Comet assay and a 2.6–7.8-fold increase in the frequency of micronucleated binucleated cells by the cytokinesis-block micronucleus assay. Furthermore, repeated intraperitoneal administration of SAFO (15, 30, 45, and 60mg/kg) to mice every other day for a total of twelve doses caused a significant dose-dependent increase in mean Comet tail moment in peripheral blood leukocytes (13.3–43.4-fold) and in the frequency of micronucleated reticulocytes (1.5–5.8-fold). Repeated administration of SAFO (60mg/kg) to mice caused liver lesions manifested as a rim of ballooning degeneration of hepatocytes immediately surrounding the central vein. Our data clearly demonstrate that SAFO significantly induced cytotoxicity, DNA strand breaks, micronuclei formation both in human cells in vitro and in mice. More studies are needed to explore the role SAFO plays in safrole-induced genotoxicity. [Copyright &y& Elsevier]
– Name: AbstractSuppliedCopyright
  Label:
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  Data: <i>Copyright of Mutation Research - Genetic Toxicology & Environmental Mutagenesis is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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      – Type: doi
        Value: 10.1016/j.mrgentox.2011.09.014
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      – Code: eng
        Text: English
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        PageCount: 8
        StartPage: 234
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      – SubjectFull: Genetic toxicology
        Type: general
      – SubjectFull: Cell-mediated cytotoxicity
        Type: general
      – SubjectFull: Sassafras
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      – SubjectFull: Electrophiles
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      – SubjectFull: Plant metabolites
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      – SubjectFull: Liver cells
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      – SubjectFull: Liver tumors
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      – SubjectFull: Cytokinesis
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      – TitleFull: Safrole-2′,3′-oxide induces cytotoxic and genotoxic effects in HepG2 cells and in mice
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              Text: Dec2011
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