In Vitro Metabolic Transformation of Pharmaceuticals by Hepatic S9 Fractions from Common Carp (Cyprinus carpio)

Abstract

Water from wastewater treatment plants contains concentrations of pharmaceutically active compounds as high as micrograms per liter, which can adversely affect fish health and behavior, and contaminate the food chain. Here, we tested the ability of the common carp hepatic S9 fraction to produce the main metabolites from citalopram, metoprolol, sertraline, and venlafaxine. Metabolism in fish S9 fractions was compared to that in sheep. The metabolism of citalopram was further studied in fish. Our results suggest a large difference in the rate of metabolites formation between fish and sheep. Fish hepatic S9 fractions do not show an ability to form metabolites from venlafaxine, which was also the case for sheep. Citalopram, metoprolol, and sertraline were metabolized by both fish and sheep S9. Citalopram showed concentration-dependent N-desmethylcitalopram formation with Vmax = 1781 pmol/min/mg and Km = 29.7 μM. The presence of ellipticine, a specific CYP1A inhibitor, in the incubations reduced the formation of N-desmethylcitalopram by 30–100% depending on the applied concentration. These findings suggest that CYP1A is the major enzyme contributing to the formation of N-desmethylcitalopram. In summary, the results from the present in vitro study suggest that common carp can form the major metabolites of citalopram, metoprolol, and sertraline.

Development of a method for assessing the accumulation and metabolization of antidepressant drugs in zebrafish (Danio rerio) eleutheroembryos

“…Some in vitro studies carried out with human liver microsomes showed that citalopram can be metabolized by the isozyme of the cytochrome P450 to N-desmethylcitalopram, with a ratio of 5-10-fold for the metabolite [18]. Another in vitro study carried out with common carp (Cyprinus carpio) hepatic S9 fractions also showed the biotransformation of citalopram and sertraline into their major metabolites desmethylcitalopram and norsertraline by the isozyme of the cytochrome P450 [17].…”

“…Because biotransformation has the potential to reduce chemical accumulation within an organism, a question of particular concern is whether aquatic biota can appreciably metabolize these compounds. Several studies have demonstrated the metabolization of SSRIs in cell lines [17][18][19] and adult fish [11,[20][21][22], but only few research studies have been published concerning the bioaccumulation and metabolization of SSRIs in the early stages of the fish life cycle [23,24]. There is growing evidence that pollutant metabolites maintain bioactive moieties, and some are more hydrophobic and exhibit similar or even greater toxicity.…”