The interference of pharmaceuticals with endogenous and xenobiotic metabolizing enzymes in carp liver: an in-vitro study.
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.
Thibaut
Rémi
R
Environment Chemistry Department, IIQAB-CSIC, C/Jordi Girona, Barcelona, Spain. rthqam@cid.csic.es
Schnell
Sabine
S
Porte
Cinta
C
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D002347:Carps; D002384:Catalysis; D002995:Clofibric Acid / Q000737:chemistry*; D004008:Diclofenac / Q000494:pharmacology; D015248:Gemfibrozil / Q000494:pharmacology; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000187:drug effects*; D008110:Liver Extracts / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000032:analysis* / Q000737:chemistry; D013347:Subcellular Fractions / Q000378:metabolism; D015238:Sulfotransferases / Q000378:metabolism; D015262:Xenobiotics / Q000494:pharmacology*
D000928:Antidepressive Agents; D008055:Lipids; D008110:Liver Extracts; D004364:Pharmaceutical Preparations; D015262:Xenobiotics; D004008:Diclofenac; D002995:Clofibric Acid; D015238:Sulfotransferases; D015248:Gemfibrozil