Four triazole fungicides used in agricultural or pharmaceutical applications were examined for hepatotoxic effects in mouse liver. Besides organ weight, histopathology, and cytochrome P450 (CYP) enzyme induction, DNA microarrays were used to generate gene expression profiles and hypotheses on potential mechanisms of action for this class of chemicals. Adult male CD-1 mice were exposed daily for 14 days to fluconazole, myclobutanil, propiconazole, or triadimefon at three dose levels by oral gavage. Doses were based on previous studies that resulted in liver hypertrophy or hepatotoxicity. All four triazoles caused hepatocyte hypertrophy, and all except triadimefon increased relative liver/body weight ratios at the middle and high dose levels. CYP enzyme activities were also induced by all four triazoles at the middle and high doses as measured by the dealkylations of four alkoxyresorufins, although some differences in substrate specificity were observed. Consistent with this common histopathology and biochemistry, several CYP and xenobiotic metabolizing enzyme (XME) genes were differentially expressed in response to all four (Cyp2d26 and Cyp3a11), or three of the four (Cyp2c40, Cyp2c55, Ces2, Slco1a4) triazoles. Differential expression of numerous other CYP and XME genes discriminated between the various triazoles, consistent with differences in CYP enzyme activities, and indicative of possible differences in mechanisms of hepatotoxicity or dose response. Multiple isoforms of Cyp1a, 2b, 2c, 3a, and other CYP and XME genes regulated by the nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) were differentially expressed following triazole exposure. Based on these results, we expanded on our original hypothesis that triazole hepatotoxicity was mediated by CYP induction, to include additional XME genes, many of which are modulated by CAR and PXR.
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http://dx.doi.org/10.1016/j.taap.2006.02.016 | DOI Listing |
Sci Total Environ
November 2023
GENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government, PTS Granada, Granada, Spain; University of Granada, Department of Biochemistry and Molecular Biology III and Immunology, Faculty of Medicine, PTS, Granada, Spain; Biosanitary Research Institute, ibs.GRANADA, Granada, Spain.
Int J Mol Sci
December 2022
Department of Analytical, Environmental and Forensic Sciences, School of Cancer & Pharmaceutical Sciences, King's College London, London SE1 9NH, UK.
Exp Gerontol
November 2022
Center for Computational Toxicology and Exposure, US EPA, Research Triangle Park, NC 27711, United States of America. Electronic address:
There is a need to characterize the potential susceptibility of older adults to toxicity from environmental chemical exposures. Liver xenobiotic metabolizing enzymes (XMEs) play important roles in detoxifying and eliminating xenobiotics. We examined global gene expression in the livers of young (21-45 years) and old (69+ years) men and women.
View Article and Find Full Text PDFSci Total Environ
August 2020
GENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government, PTS Granada, Granada, Spain; University of Granada, Department of Biochemistry and Molecular Biology III, Faculty of Medicine, PTS, Granada, Spain.
Cancer is considered a complex disease that in many cases results from the interaction between chemical exposures, either from environmental or dietary sources, and genetic polymorphisms of xenobiotic-metabolizing enzymes (XME) or antioxidant enzymatic defenses. This study explored associations and interactions between genetic and environmental risk factors on the risk of prostate cancer (PCa) in 323 subjects that underwent prostate biopsy due to prostate specific antigen (PSA) levels above 4 ng/ml (161 PCa and 162 non-PCa). Eleven genes involved directly or indirectly in xenobiotic detoxification, oxidative stress and estrogen signaling were studied (GSTM1, GPX1 (rs1050450 and rs17650792), NAT2 (rs1801280), TXNRD1 (rs7310505), PRDX3 (rs3740562), CYP17A1 (rs743572), PON1 (rs662), SOD1 (rs10432782), SOD2 (rs4880), CAT (rs1001179), and ESR1 (rs746432)).
View Article and Find Full Text PDFGenes (Basel)
May 2019
Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036 Rende, Italy.
Xenobiotic-metabolizing enzymes (XME) mediate the body's response to potentially harmful compounds of exogenous/endogenous origin to which individuals are exposed during their lifetime. Aging adversely affects such responses, making the elderly more susceptible to toxics. Of note, XME genetic variability was found to impact the ability to cope with xenobiotics and, consequently, disease predisposition.
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