The Connection of Azole Fungicides with Xeno-Sensing Nuclear Receptors, Drug Metabolism and Hepatotoxicity
Azole fungicides, especially triazole compounds, are widely used in agriculture and as pharmaceuticals. For a considerable number of agricultural azole fungicides, the liver has been identified as the main target organ of toxicity. A number of previous studies points towards an important role of nuc...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-05-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/5/1192 |
| _version_ | 1797568293081448448 |
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| author | Philip Marx-Stoelting Constanze Knebel Albert Braeuning |
| author_facet | Philip Marx-Stoelting Constanze Knebel Albert Braeuning |
| author_sort | Philip Marx-Stoelting |
| collection | DOAJ |
| description | Azole fungicides, especially triazole compounds, are widely used in agriculture and as pharmaceuticals. For a considerable number of agricultural azole fungicides, the liver has been identified as the main target organ of toxicity. A number of previous studies points towards an important role of nuclear receptors such as the constitutive androstane receptor (CAR), the pregnane-X-receptor (PXR), or the aryl hydrocarbon receptor (AHR), within the molecular pathways leading to hepatotoxicity of these compounds. Nuclear receptor-mediated hepatic effects may comprise rather adaptive changes such as the induction of drug-metabolizing enzymes, to hepatocellular hypertrophy, histopathologically detectable fatty acid changes, proliferation of hepatocytes, and the promotion of liver tumors. Here, we present a comprehensive review of the current knowledge of the interaction of major agricultural azole-class fungicides with the three nuclear receptors CAR, PXR, and AHR in vivo and in vitro. Nuclear receptor activation profiles of the azoles are presented and related to histopathological findings from classic toxicity studies. Important issues such as species differences and multi-receptor agonism and the consequences for data interpretation and risk assessment are discussed. |
| first_indexed | 2024-03-10T19:54:25Z |
| format | Article |
| id | doaj.art-5487efc0d6bd4d35834c990fb04bd0f8 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T19:54:25Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-5487efc0d6bd4d35834c990fb04bd0f82023-11-20T00:02:44ZengMDPI AGCells2073-44092020-05-0195119210.3390/cells9051192The Connection of Azole Fungicides with Xeno-Sensing Nuclear Receptors, Drug Metabolism and HepatotoxicityPhilip Marx-Stoelting0Constanze Knebel1Albert Braeuning2German Federal Institute for Risk Assessment, Department Pesticides Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, GermanyGerman Federal Institute for Risk Assessment, Department Food Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, GermanyGerman Federal Institute for Risk Assessment, Department Food Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, GermanyAzole fungicides, especially triazole compounds, are widely used in agriculture and as pharmaceuticals. For a considerable number of agricultural azole fungicides, the liver has been identified as the main target organ of toxicity. A number of previous studies points towards an important role of nuclear receptors such as the constitutive androstane receptor (CAR), the pregnane-X-receptor (PXR), or the aryl hydrocarbon receptor (AHR), within the molecular pathways leading to hepatotoxicity of these compounds. Nuclear receptor-mediated hepatic effects may comprise rather adaptive changes such as the induction of drug-metabolizing enzymes, to hepatocellular hypertrophy, histopathologically detectable fatty acid changes, proliferation of hepatocytes, and the promotion of liver tumors. Here, we present a comprehensive review of the current knowledge of the interaction of major agricultural azole-class fungicides with the three nuclear receptors CAR, PXR, and AHR in vivo and in vitro. Nuclear receptor activation profiles of the azoles are presented and related to histopathological findings from classic toxicity studies. Important issues such as species differences and multi-receptor agonism and the consequences for data interpretation and risk assessment are discussed.https://www.mdpi.com/2073-4409/9/5/1192aryl hydrocarbon receptorconstitutive androstane receptorcytochrome P450enzyme inductionhepatotoxicityliver hypertrophy |
| spellingShingle | Philip Marx-Stoelting Constanze Knebel Albert Braeuning The Connection of Azole Fungicides with Xeno-Sensing Nuclear Receptors, Drug Metabolism and Hepatotoxicity Cells aryl hydrocarbon receptor constitutive androstane receptor cytochrome P450 enzyme induction hepatotoxicity liver hypertrophy |
| title | The Connection of Azole Fungicides with Xeno-Sensing Nuclear Receptors, Drug Metabolism and Hepatotoxicity |
| title_full | The Connection of Azole Fungicides with Xeno-Sensing Nuclear Receptors, Drug Metabolism and Hepatotoxicity |
| title_fullStr | The Connection of Azole Fungicides with Xeno-Sensing Nuclear Receptors, Drug Metabolism and Hepatotoxicity |
| title_full_unstemmed | The Connection of Azole Fungicides with Xeno-Sensing Nuclear Receptors, Drug Metabolism and Hepatotoxicity |
| title_short | The Connection of Azole Fungicides with Xeno-Sensing Nuclear Receptors, Drug Metabolism and Hepatotoxicity |
| title_sort | connection of azole fungicides with xeno sensing nuclear receptors drug metabolism and hepatotoxicity |
| topic | aryl hydrocarbon receptor constitutive androstane receptor cytochrome P450 enzyme induction hepatotoxicity liver hypertrophy |
| url | https://www.mdpi.com/2073-4409/9/5/1192 |
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