Fenbendazole administration induces cytochrome P450 1a-dependent enzyme activities in pig liver

Abstract

Fenbendazole (FBZ), a benzymidazole (BZD) drug, is used to control gastrointestinal parasites in continuous administration in swine. This drug undergoes two sequential S-oxidations through mixed function oxidases belonging to the cytochrome P450 (CYP) and flavin-monooxygenase (FMO) families. Also, BZD-containing drugs may induce the CYP1A subfamily. This work aimed to evaluate in vitro the effect of FBZ on CYP1A-dependent enzyme activities in pig liver. Five (5) piglets remained untreated (controls) and other six (6) were treated with a FBZ commercial powder mixed with food, in two dosing events repeated for 10 consecutive days, as usually is recommended. Both groups were fed ad libitum for 10 days and then euthanized for preparation of liver microsomes. FBZ and its metabolites, oxfendazole (OFZ) and fenbendazole sulphone (FBZSO2), were detected in the systemic circulation of treated piglets. Mean plasma AUCs (µg.day/mL) were 0.28±0.08 (FBZ), 4.10±0.58 (OFZ) and 4.56±1.01 (FBZSO2). Concentrations (µg/g) of FBZ, OFZ and FBZSO2 in liver parenchyma were 4.66±1.59, 3.11±1.06 and 2.30±0.99, respectively. In liver microsomes from treated animals, CYP1A-dependent enzyme activities, 7-ethoxuresorufin O-deethylase and methoxyresorufin O-demethylase, increased 24.5-fold (p=0.003) and 17.2-fold (p=0.001), respectively. The participation of the CYP pathway in the S-oxidation of FBZ into OFZ was also enhanced (3.4-fold, p=0.004) in piglets which received the anthelmintic with food (61.8±19.5 pmol/min.mg) compared to controls (18.0±6.0 pmol/min.mg). Thus, FBZ may auto-induce its own metabolism though the CYP1A pathway. This fact may also affect the fate of other xenobiotics that share the same metabolic pattern, like aflatoxin B1 present in certain pig foodstuffs.