The Interference of Pharmaceuticals with Endogenous and Xenobiotic Metabolizing Enzymes in Carp Liver:  An In-Vitro Study

Abstract

The interactions of fibrate (clofibrate, fenofibrate, bezafibrate, gemfibrozil), antiinflammatory (ibuprofen, diclofenac, naproxen, ketoprofen), and anti-depressive (fluoxetine,fluvoxamine, paroxetine) drugs with CYP catalyzed pathways (CYP1A, CYP3A-, CYP2K-, and CYP2M-like) and Phase II activities (UDP-glucuronosyltransferases and sulfotransferases), involved in both xenobiotic and endogenous metabolism in fish, were investigated in-vitro by incubating carp liver subcellular fractions in the presence of the substrate and the selected drug. Anti-depressive drugs were strong inhibitors of CYP1A (92-94% inhibition), CYP3A-like (69-80% inhibition), and CYP2K-like (36-69% inhibition) catalyzed activities, while antiinflammatory drugs were potent CYP2M-like inhibitors (32-74% inhibition). Among the lipid regulators, gemfibrozil strongly inhibited CYP2M-catalyzed activity (91% inhibition) and other CYP isoforms (CYP1A and CYP3A-like). Additionally, glucuronidation of naphthol and testosterone were targeted by antiinflammatory drugs, and to a lesser extent, by fibrate drugs (48-78% inhibition). No significant alteration on sulfotransferase activities was observed, apart from a minor inhibitory effect of clofibrate, gemfibrozil, and fluoxetine on the sulfation of estradiol. Overall, gemfibrozil, diclofenac, and the three anti-depressive drugs appear to be the pharmaceuticals with the highest potential to interfere with fish metabolic systems.

Effective kinetics of schisandrin B on serum/hepatic triglyceride and total cholesterol levels in mice with and without the influence of fenofibrate

“…The reduction of the E max value and the augmentation of the K D value of the effective kinetics of schisandrin B on hepatic index by fenofibrate treatment suggest that the hepatotrophic action of these two drugs may be mediated by a similar biochemical mechanism. In this regard, the hepatocellular hypertrophic effect of fibric acid analogs (including fenofibrate) was found to be related to the induction of xenobiotic-metabolizing enzymes and activation of peroxisome proliferator-activated receptors, which play important roles in the metabolic regulation of lipids (Neumeier et al 2006;Thibaut et al 2006;Ren et al 2010). While the mechanism involved in the hepatotrophic action of schisandrin B remains to be determined, it may be related to the induction of xenobiotic-and/or lipidmetabolizing enzymes by this compound.…”

Physiological Endpoints for Potential SSRI Interactions in Fish

“…Presumably, the enzymes responsible for SSRI metabolism in fish also belong to the cytochrome P-450 superfamily, as these key metabolizing enzymes are highly conserved among vertebrates and may display a similar substrate specificity. 26 In the Japanese puffer fish (Takifugu rubripes), also known as fugu, orthologous nucleotide sequences from 17 of 18 mammalian P450 families were detected. 27 Even though McArthur et al 28 observed that teleost and mammalian P450 genes belonging to the CYP3A subfamily have undergone independent diversification in the course of gene duplication events that may have coincided with the acquisition of new functions, it can be expected that SSRIs may interact with and inhibit some P450 isoenzymes in fish.…”

Interspecies comparison of selected pollution biomarkers in dreissenid spp. inhabiting pristine and moderately polluted sites

“…Another important issue that has to be considered here is the fact that certain ubiquitous contaminants as pharmaceuticals (diclofenac, carbamazepine, clofibrate etc. ), organochlorine residues and some metallic contaminants (organotins, mercury) were proven to inhibit the CYP-like enzymes and associated mixed function oxidase components (Thibaut et al, 2006;Lavado et al, 2006;Edwards et al, 2007;Faria et al, 2010) in several biological models. Thus, for sites as harbours, which are usually affected by complex mixtures of contaminants, the antagonism of chemicals on the EROD activity of aquatic biota might also be expected.…”