Further insights into the hepatic metabolism of benzimidazole anthelmintics in sheep: Impact of dexamethasone-mediated induction of the cytochrome P450 3A pathway

Abstract

The anthelmintics albendazole (ABZ) and fenbendazole (FBZ) undergo enantiospecific hepatic S‑oxygenation into sulfoxide metabolites, albendazole sulfoxide (ABZSO) and oxfendazole (OFZ), respectively. Flavin-monooxygenases (FMO) and cytochromes P450 (CYP) are involved in this process. While most is known on the FMO-dependent S‑oxygenation of both anthelmintics, the participation of different CYPs remains to be elucidated. This research investigated the role of the CYP3A pathway in the S‑oxygenation of ABZ and FBZ in sheep liver, particularly following induction with the glucocorticoid dexamethasone (DEX). Liver microsomes from DEX-treated (3 mg/kg/day for seven days) and untreated (control) sheep were prepared to determine monooxygenase activities and the involvement of the FMO and CYP pathways in the enantiospecific production of (+) and (−) sulfoxide enantiomers. DEX treatment significantly induced CYP3A marker catalytic activities, triacetyl-oleandomycin (TAO) and erythromycin (ERTM) N-demethylations [3.5-fold (p = 0.01) and 4.8-fold (p = 0.02), respectively]. Additionally, the FMO-dependent methimazole (MTZ) S‑oxygenase activity decreased by 28 % (p = 0.02) in DEX-treated sheep. A significant reduction in FMO-dependent production rates of (+) ABZSO (61 %, p < 0.05) and (+) OFZ (71 %, p < 0.05) was observed in DEX-treated sheep compared to controls. No changes in the FMO-mediated production of (−) enantiomers were observed between both experimental groups. DEX treatment induced the CYP-specific production of (−) ABZSO (2.5-fold, p = 0.03) and both (+) OFZ (1.8-fold, p = 0.04) and (−) OFZ (3-fold, p = 0.04). This work shows some distinctive enantiospecific metabolic differences between the two anthelmintic drugs and further contributes to understanding the pathways involved in their hepatic metabolism.