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Enantiospecific effects of ketoconazole on aryl hydrocarbon receptor
A. Novotna, M. Korhonova, I. Bartonkova, AA. Soshilov, MS. Denison, K. Bogdanova, M. Kolar, P. Bednar, Z. Dvorak,
Language English Country United States
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
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- MeSH
- Antifungal Agents chemistry pharmacology MeSH
- Hep G2 Cells MeSH
- Candida drug effects MeSH
- Cytochrome P-450 CYP1A1 genetics metabolism MeSH
- Cytochrome P-450 CYP1A2 genetics metabolism MeSH
- Transcription, Genetic drug effects MeSH
- Hepatocytes drug effects metabolism MeSH
- Ketoconazole chemistry pharmacology MeSH
- Middle Aged MeSH
- Humans MeSH
- RNA, Messenger genetics metabolism MeSH
- Guinea Pigs MeSH
- Mice MeSH
- Receptors, Aryl Hydrocarbon metabolism MeSH
- Aged MeSH
- Signal Transduction drug effects MeSH
- Stereoisomerism MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Guinea Pigs MeSH
- Male MeSH
- Mice MeSH
- Aged MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
Azole antifungal ketoconazole (KET) was demonstrated to activate aryl hydrocarbon receptor (AhR). Since clinically used KET is a racemic mixture of two cis-enantiomers (2R,4S)-(+)-KET and (2S,4R)-(-)-KET, we examined the effects of KET enantiomers on AhR signaling pathway. (+)-KET dose-dependently activated AhR in human gene reporter cell line AZ-AHR, and displayed 5-20× higher agonist activity (efficacy), as compared to (-)-KET; both enantiomers were AhR antagonists with equal potency (IC50). Consistently, (+)-KET strongly induced CYP1A1 mRNA and protein in human HepG2 cells, while (-)-KET exerted less than 10% of (+)-KET activity. In primary human hepatocytes, both enantiomers preferentially induced CYP1A2 over CYP1A1 mRNA and protein, and the potency of (+)-KET was slightly higher as compared to (-)-KET. Ligand binding assay with guinea pig liver cytosols revealed that both (+)-KET and (-)-KET are weak ligands of AhR that displaced [3H]-TCDD with comparable potency. Similarly, both enantiomers weakly transformed AhR to DNA-binding form with similar potency, as showed by EMSA, in guinea pig liver cytosolic extracts and nuclear extracts from mouse Hepa-1 cells. We also examined effects of KET on glucocorticoid receptor (GR), a regulator of AhR activity. Both KET enantiomers antagonized GR with similar potency, as revealed by gene reporter assay in AZ-GR cell line and down-regulation of tyrosine aminotransferase mRNA in human hepatocytes. Finally, we demonstrate enantiospecific antifungal activities of KET enantiomers in six Candida spp. strains. In conclusion, the significance of current study is providing the first evidence of enatiospecific effects of cis-enantiomers of ketoconazole on AhR-CYP1A pathway.
References provided by Crossref.org
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