Abstract
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.
Highlights
Azole fungicides, especially triazoles, are widely used in agriculture as antifungal agents in plant protection products [1]
The common fungistatic mode of action of the azoles is based on the inhibition of the enzyme 14α sterol demethylase, which belongs to the cytochrome P450 (CYP) family and is known as CYP51 [2]
We reviewed the literature for interaction with the three receptors aryl hydrocarbon receptor (AHR), constitutive androstane receptor (CAR), and pregnane-X-receptor (PXR), as those constitute the most prominent xeno-sensing receptors involved in the majority of regulation processes of drug-metabolizing enzymes in the liver
Summary
Especially triazoles, are widely used in agriculture as antifungal agents in plant protection products [1]. In addition to the intended action, azoles induce side effects in mammals, for example by inhibition of mammalian CYP enzymes, or by interference with different ligand-activated nuclear receptors and subsequent alterations in the expression of the corresponding nuclear receptor target genes [4]. These target genes comprise, amongst others, various CYP enzymes that play an important role in xenobiotic metabolism. CAG contains azoles that are teratogenic after acute exposure These adverse effects are attributed to the inhibition of key enzymes involved in hormonal balance, the interaction with steroid hormone receptors [7], and the metabolism of retinoic acid [8]. Nuclear receptor-mediated hepatotoxicity of agricultural azole fungicides is summarized and discussed in the present review
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