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- Beijer, Kristina, 1980-, et al.
(författare)
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Azoles additively inhibit cytochrome P450 1 (EROD) and 19 (aromatase) in rainbow trout (Oncorhynchus mykiss)
- 2018
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Ingår i: Aquatic Toxicology. - : Elsevier BV. - 0166-445X .- 1879-1514. ; 198, s. 73-81
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Tidskriftsartikel (refereegranskat)abstract
- Antifungal azoles are widely used in medicine, agriculture, and material protection and several antifungal azoles have been found in environmental samples. Although these compounds were designed to inhibit fungal enzymes such as lanosterol-14-demethylase (cytochrome P450 (CYP) 51), it is well established that the inhibitory actions of azoles are not specific for fungal CYP isozymes.We refined a gill filament assay to determine the inhibition of CYP1, measured as reduced 7-ethoxyresorufin-O-deethylase (EROD) activity, in rainbow trout (Oncorhynchus mykiss) gill tissue ex vivo. The advantage of this method is that both induction and inhibition of EROD are performed ex vivo. Among thirteen azoles studied, the five that caused the strongest inhibition of gill EROD activity at a concentration of 5 μM were selected for concentration–response assessment. These compounds (bifonazole, clotrimazole, imazalil, miconazole, and prochloraz) showed IC50 values ranging from 0.1 to 1.5 μM. CYP19 (aromatase) inhibition was measured using microsomes from rainbow trout brains. Concentration-response curves for CYP19 inhibition were determined for letrozole, bifonazole, clotrimazole, imazalil, miconazole and prochloraz, which gave IC50 values ranging from 0.02 to 3.3 μM. It was further found that mixtures of the five most potent azoles reduced both CYP1 and 19 catalytic activity in an additive fashion (IC50 = 0.7 μM and 0.6 μM, in the respective assay). Bifonazole (IC50 = 0.1 μM) is not previously known to inhibit CYP1 activity.The additive inhibition of CYP1 and CYP19 catalytic activity is an important finding of the present study. We conclude that this additive action of azoles could mediate adverse impacts on CYP regulated physiological functions in environmentally exposed fish.
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| 3. |
- Beijer, Kristina, et al.
(författare)
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Removal of pharmaceuticals and unspecified contaminants in sewage treatment effluents by activated carbon filtration and ozonation : Evaluation using biomarker responses and chemical analysis
- 2017
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Ingår i: Chemosphere. - : Elsevier BV. - 0045-6535 .- 1879-1298. ; 176, s. 342-351
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Tidskriftsartikel (refereegranskat)abstract
- Traces of active pharmaceutical ingredients (APIs) and other chemicals are demonstrated in effluents from sewage treatment plants (STPs) and they may affect quality of surface water and eventually drinking water. Treatment of effluents with granular activated carbon (GAC) or ozone to improve removal of APIs and other contaminants was evaluated at two Swedish STPs, Kappala and Uppsala (88 and 103 APIs analyzed). Biomarker responses in rainbow trout exposed to regular and additionally treated effluents were determined. GAC and ozone treatment removed 87-95% of the total concentrations of APIs detected. In Kappala, GAC removed 20 and ozonation (7 g O-3/m(3)) 21 of 24 APIs detected in regular effluent. In Uppsala, GAC removed 25 and ozonation (5.4 g O-3/m(3)) 15 of 25 APIs detected in effluent. GAC and ozonation also reduced biomarker responses caused by unidentified pollutants in STP effluent water. Elevated ethoxyresorufin-O-deethylase (EROD) activity in gills was observed in fish exposed to effluent in both STPs. Gene expression analysis carried out in Kappala showed increased concentrations of cytochrome P450 (CYP1A5 and CYP1C3) transcripts in gills and of CYP1As in liver of fish exposed to effluent. In fish exposed to GAC- or ozone-treated effluent water, gill EROD activity and expression of CYP1As and CYP1C3 in gills and liver were generally equal to or below levels in fish held in tap water. The joint application of chemical analysis and sensitive biomarkers proved useful for evaluating contaminant removal in STPs with new technologies.
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| 5. |
- Jönsson, Maria E., et al.
(författare)
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Toxicity and cytochrome P450 1A mRNA induction by 6-formylindolo[3,2-b]carbazole (FICZ) in chicken and Japanese quail embryos
- 2016
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Ingår i: Comparative Biochemistry and Physiology - Part C. - : Elsevier BV. - 1532-0456 .- 1878-1659. ; 179, s. 125-136
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Tidskriftsartikel (refereegranskat)abstract
- The tryptophan derivative formylindolo[3,2-b]carbazole (FICZ) binds with high ligand affinity to the aryl hydrocarbon receptor (AHR) and is readily degraded by AHR-regulated cytochrome P450 family 1 (CYP1) enzymes. Whether in vivo exposure to FICZ can result in toxic effects has not been examined and the main objective of this study was to determine if FICZ is embryotoxic in birds. We examined toxicity and CYP1 mRNA induction of FICZ in embryos from chicken (Gallus domesticus) and Japanese quail (Coturnix japonica) exposed to FICZ (2200 jag kg(-1)) by yolk and air sac injections. FICZ caused liver toxicity, embryo mortality, and CYP1A4 and CYP1A5 induction in both species with similar potency. This is in stark contrast to the very large difference in sensitivity of these species to halogenated AHR agonists. We also exposed chicken embryos to a low dose of FICZ (4 mu g kg(-1)) in combination with a CYP inhibitor, ketoconazole (KCZ). The mixture of FICZ and KCZ was lethal while FICZ alone had no effect at 4 mu g kg(-1). Furthermore, mixed exposure to FICZ and KCZ caused stronger and more long-lasting hepatic CYP1A4 induction than exposure to each compound alone. These findings indicate reduced biotransformation of FICZ by co-treatment with KCZ as a cause for the enhanced effects although additive AHR activation is also possible. To conclude, FICZ is toxic to bird embryos and it seems reasonable that the toxicity by FICZ involves AHR activation. However, the molecular targets and biological events leading to hepatic damage and mortality are unknown.
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