In-feed drug medication in pig production: effects on xenobiotic metabolizing enzymes

Abstract

In-feed medication with the anthelmintic fenbendazole (FBZ) is routinary in pig husbandry. This drug undergoes hepatic metabolism through cytochrome P450 (CYP) and flavin-monooxygenase (FMO) enzyme families. Also, FBZ and its metabolite oxfendazole (OFZ) may induce the CYP1A subfamily. This work aimed to evaluate the effect of FBZ administration on i) CYP1A-dependent enzyme activities; ii) its own pattern of hepatic S-oxidation; iii) the metabolism of enrofloxacin (ERF) and aflatoxin B1 (AFB1). Female Landrace piglets remained untreated (n=5) or received a pre-mix of FBZ in feed as usually is recommended for 9 days (n=6). Liver microsomes from control and FBZ-treated animals were used for i) CYP content determination; ii) monitoring CYP1A-dependent enzyme activities, 7-ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-demethylase (MROD); iii) measurement of FBZ (50 µM) S-oxidation, ERF (50 µM) conversion into ciprofloxacin (CPF) and AFB1 (16 nM) disappearance. In liver microsomes from treated animals, EROD and MROD increased 20-fold (p=0.002) and 19-fold (p=0.001), respectively. An enhanced (3-fold, p=0.0037) participation of the CYP pathway in the hepatic S-oxidation of FBZ into OFZ was observed in the liver of piglets receiving FBZ compared to controls. ERF conversion into CPF increased (p=0.014) from 26.5±8.4 pmol/min.nmol CYP (controls) to 139.4±60.1 pmol/min. nmol CYP (FBZ-treated). The rate of disappearance of AFB1 in FBZ-treated pigs was 79% higher (p=0.036) compared to control animals. An auto-induction of the CYP1A-dependent S-oxidation of FBZ towards its active metabolite OFZ was observed. The in-feed medication with FBZ may cause potential metabolic interactions with the antimicrobial ERF and the mycotoxin AFB1. Enzyme induction caused by the anthelmintic may modify the pharmacokinetic behaviour of ERF and CPF. In addition, induction of the CYP1A-dependent metabolism of AFB1 may increase the production of a hepatotoxic AFB1-derived epoxide.