Cytochrome P450 Inhibition by Antimicrobials and Their Mixtures in Rainbow Trout Liver Microsomes In Vitro

Abstract

Antimicrobials are ubiquitous in the environment and can bioaccumulate in fish. In the present study, we determined the half-maximal inhibitory concentrations (IC50) of 7 environmentally abundant antimicrobials (ciprofloxacin, clarithromycin, clotrimazole, erythromycin, ketoconazole, miconazole, and sulfamethoxazole) on the cytochrome P450 (CYP) system in rainbow trout (Oncorhynchus mykiss) liver microsomes, using 7-ethoxyresorufin O-deethylation (EROD, CYP1A) and 7-benzyloxy-4-trifluoromethylcoumarin O-debenzylation (BFCOD, CYP3A) as model reactions. Apart from ciprofloxacin and sulfamethoxazole, all antimicrobials inhibited either EROD or BFCOD activities or both at concentrations <500 µM. Erythromycin was the only selective and time-dependent inhibitor of BFCOD. Compared with environmental concentrations, the IC50s of individual compounds were generally high (greater than milligrams per liter); but as mixtures, the antimicrobials resulted in strong, indicatively synergistic inhibitions of both EROD and BFCOD at submicromolar (~micrograms per liter) mixture concentrations. The cumulative inhibition of the BFCOD activity was detectable even at picomolar (~nanograms per liter) mixture concentrations and potentiated over time, likely because of the strong inhibition of CYP3A by ketoconazole (IC50 = 1.7 ± 0.3 µM) and clotrimazole (IC50 = 1.2 ± 0.2 µM). The results suggest that if taken up by fish, the mixtures of these antimicrobials may result in broad CYP inactivation and increase the bioaccumulation risk of any other xenobiotic normally cleared by the hepatic CYPs even at biologically relevant concentrations.

IK Channel-Independent Effects of Clotrimazole and Senicapoc on Cancer Cells Viability and Migration

“…It has been known since the late 1990s that the IK channel is blocked by the scorpion toxin charybdotoxin and by clotrimazole, which is a member of the imidazole antimycotics family [13,15,[18][19][20]. Clotrimazole blocks the channel very efficiently but is also an inhibitor of cytochrome P450 (CYP) enzymes from different species (see for example [21][22][23][24][25]). In order to obtain a more selective molecule, Wulff and colleagues used a rational design strategy to develop a clotrimazole analog lacking the imidazole ring, which is strictly required for cytochrome P450 inhibition, obtaining the molecule known as TRAM-34 (IC 50 = 20 nM) [26].…”

Occurrence, Distribution, and Trophic Transfer of Pharmaceuticals and Personal Care Products in the Bohai Sea

“…Thus, this is the first report on the trophodynamics of MCZ and ACE. Considering that the absorption of MCZ by fish may cause the inactivation of broad-spectrum cytochrome P450 in the liver, the magnification of MCZ may increase the risk to these organisms.…”

Predicted Environmental Risk Assessment of Antimicrobials with Increased Consumption in Portugal during the COVID-19 Pandemic; The Groundwork for the Forthcoming Water Quality Survey

“…Furthermore, this molecule may inhibit the CYP activity of marine species and thereby interfere with the hepatic clearance of xenobiotics from those species. Thus, this molecule may also pose an environmental risk similar to those detected with other known CYP inhibitors belonging to the antifungal group [ 67 ]. Nevertheless, no risk was observed with the assessment approach used in the present study.…”