Bioavailability of the imidazole antifungal agent clotrimazole and its effects on key biotransformation genes in the common carp (Cyprinus carpio)

• Published in: Aquatic toxicology 2014-07, Vol.152, p.57-65
• Main Authors: Corcoran, Jenna, Lange, Anke, Cumming, Rob I., Owen, Stewart F., Ball, Jonathan S., Tyler, Charles R., Winter, Matthew J.
• Format: Article
• Language: English
• Subjects: Agnatha. Pisces; Animal, plant and microbial ecology; Animals; Antifungal Agents - analysis; Antifungal Agents - toxicity; Applied ecology; Biological and medical sciences; Biotransformation - genetics; Carps - genetics; Carps - physiology; Clotrimazole; Clotrimazole - analysis; Clotrimazole - toxicity; Cyprinus carpio; Ecotoxicology, biological effects of pollution; Effects of pollution and side effects of pesticides on vertebrates; Fish; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Liver - chemistry; Liver - drug effects; Pregnane X receptor (PXR); Water Pollutants, Chemical - analysis; Water Pollutants, Chemical - toxicity
• ISSN: 0166-445X; 1879-1514
• DOI: 10.1016/j.aquatox.2014.03.016

•Clotrimazole concentrates in the plasma and liver of common carp exposed via water.•The calculated BCF for clotrimazole in the liver was between 144 and 1691.•Measurable levels of clotrimazole remained in the liver after 4 days depuration.•Clotrimazole exposure induced expression of a number of biotransformation genes.•Expression of drug transporter genes was altered at an environmental relevant concentration. Clotrimazole (CTZ) is a persistent imidazole antifungal agent which is frequently detected in the aquatic environment and predicted to bio-concentrate in fish. Common carp (Cyprinus carpio) were exposed to mean measured concentrations of either 1.02 or 14.63μgl−1 CTZ for 4 and 10 days, followed by a depuration period of 4 days in a further group of animals. Following each exposure regimen, plasma and liver CTZ concentrations were measured. Mean measured plasma concentrations of CTZ in animals exposed to the lower concentration of CTZ were 30 and 44μgl−1 on days 4 and 10, respectively, and in the higher concentration were 318 and 336μgl−1. Mean measured liver levels in the same animals were 514, 1725, 2111 and 7017μgl−1 suggesting progressive hepatic accumulation. Measurement of CTZ in plasma after depuration suggested efficient elimination within 4 days, but appreciable levels of CTZ remained in the liver after depuration suggesting a degree of persistence in this tissue. In addition we measured responses of a number of key hepatic detoxification gene targets in the liver associated with the transcription factor pregnane X receptor (PXR); namely cyp450s 2k and 3a, glutathione-S-transferases a and p (gsta and p), and drug transporters multidrug resistance protein1 (mdr1), and MDR-related protein2 (mrp2). CTZ is a potent ligand of the PXR in humans and there is some evidence of PXR activation following exposure to CTZ in fish. The highest concentration of CTZ was adopted to explore the potential for alterations to detoxification gene expression in fish at a pharmacologically relevant dose level, and the lower concentration is within the range reported in effluents from waste water treatment works (WWTW). The genes for all biotransformation enzymes were up-regulated after exposure to the higher concentration of CTZ for 10 days, and alterations in expression occurred for the drug transporter genes mdr1 and mrp2 following exposure to the lower concentration of 1.02μgl−1 CTZ (mean measured concentration). These data support the potential for CTZ to induce