PMID- 30819427 OWN - NLM STAT- MEDLINE DCOM- 20190423 LR - 20190423 IS - 1532-2971 (Electronic) IS - 1090-0233 (Linking) VI - 245 DP - 2019 Mar TI - Effects of fenbendazole and triclabendazole on the expression of cytochrome P450 1A and flavin-monooxygenase isozymes in bovine precision-cut liver slices. PG - 61-69 LID - S1090-0233(18)30304-6 [pii] LID - 10.1016/j.tvjl.2019.01.001 [doi] AB - Combinations of the anthelmintics fenbendazole (FBZ) and triclabendazole (TCBZ) have shown enhanced efficacy against the liver fluke Fasciola hepatica. This study aimed to measuring the constitutive expression of CYP1A1, CYP1A2, FMO1 and FMO3, thought to be involved in the metabolism of those compounds, by using an absolute quantitative real time (RT)-PCR approach in bovine precision-cut liver slices (PCLS). It also aimed to characterize the effects of FBZ and TCBZ (alone and in combination) on the expression and activity of the aforementioned isozymes. Both FMO1 and FMO3 were equally represented in control PCLS, whereas CYP1A2 was expressed more than CYP1A1 (P<0.05). PCLS cultured in the presence of beta naphthoflavone (beta-NF; CYP1A inducer) had higher mRNA levels of CYP1A1, CYP1A2, FMO1 and FMO3 (P<0.05). No clear-cut evidence of transcriptional effects of the anthelmintics were recorded. After incubation of PCLS with FBZ, there was a significant increase (P<0.05) vs. controls and TBCZ was observed for CYP1A1. PCLS treated with FBZ showed a higher (P<0.05) expression of CYP1A2 compared to controls, TCBZ alone, and the combination FBZ+TCBZ. The gene expression profiles of FMO1 and FMO3 were not affected by the presence of the anthelmintics; the only exception was an upregulation of FMO3 by TCBZ alone. The observed transcriptional effects of the xenobiotics were not mirrored by increased enzyme activities using prototypical substrates of the isozymes under study. Although further confirmatory studies are needed, these results suggest that PCLS represent an alternative in vitro tool for studies on the expression, regulation and function of relevant xenobiotic-metabolizing enzymes in cattle. CI - Copyright (c) 2019 Elsevier Ltd. All rights reserved. FAU - Mate, L AU - Mate L AD - Laboratorio de Farmacologia, Centro de Investigacion Veterinaria de Tandil (CIVETAN), CONICET-CICPBA-UNCPBA, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro (FCV-UNCPBA), Tandil, Argentina. Electronic address: lauramate04@gmail.com. FAU - Giantin, M AU - Giantin M AD - Department of Comparative Biomedicine and Food Science, Division of Veterinary Pharmacology and Toxicology, Viale dell'Universita 16, University of Padua, Legnaro (Padua), Italy. FAU - Viviani, P AU - Viviani P AD - Laboratorio de Farmacologia, Centro de Investigacion Veterinaria de Tandil (CIVETAN), CONICET-CICPBA-UNCPBA, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro (FCV-UNCPBA), Tandil, Argentina. FAU - Ballent, M AU - Ballent M AD - Laboratorio de Farmacologia, Centro de Investigacion Veterinaria de Tandil (CIVETAN), CONICET-CICPBA-UNCPBA, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro (FCV-UNCPBA), Tandil, Argentina. FAU - Tolosi, R AU - Tolosi R AD - Department of Comparative Biomedicine and Food Science, Division of Veterinary Pharmacology and Toxicology, Viale dell'Universita 16, University of Padua, Legnaro (Padua), Italy. FAU - Lifschitz, A AU - Lifschitz A AD - Laboratorio de Farmacologia, Centro de Investigacion Veterinaria de Tandil (CIVETAN), CONICET-CICPBA-UNCPBA, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro (FCV-UNCPBA), Tandil, Argentina. FAU - Lanusse, C AU - Lanusse C AD - Laboratorio de Farmacologia, Centro de Investigacion Veterinaria de Tandil (CIVETAN), CONICET-CICPBA-UNCPBA, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro (FCV-UNCPBA), Tandil, Argentina. FAU - Dacasto, M AU - Dacasto M AD - Department of Comparative Biomedicine and Food Science, Division of Veterinary Pharmacology and Toxicology, Viale dell'Universita 16, University of Padua, Legnaro (Padua), Italy. Electronic address: mauro.dacasto@unipd.it. FAU - Virkel, G AU - Virkel G AD - Laboratorio de Farmacologia, Centro de Investigacion Veterinaria de Tandil (CIVETAN), CONICET-CICPBA-UNCPBA, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro (FCV-UNCPBA), Tandil, Argentina. LA - eng PT - Journal Article DEP - 20190115 PL - England TA - Vet J JT - Veterinary journal (London, England : 1997) JID - 9706281 RN - 0 (Anthelmintics) RN - 0 (Isoenzymes) RN - 0 (RNA, Messenger) RN - 4784C8E03O (Triclabendazole) RN - 621BVT9M36 (Fenbendazole) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 1.13.- (Oxygenases) RN - EC 1.14.13.8 (dimethylaniline monooxygenase (N-oxide forming)) RN - EC 1.14.14.1 (Cytochrome P-450 CYP1A1) RN - EC 1.14.14.1 (Cytochrome P-450 CYP1A2) SB - IM MH - Animals MH - Anthelmintics/administration & dosage MH - *Cattle MH - Cytochrome P-450 CYP1A1/genetics MH - Cytochrome P-450 CYP1A2/genetics MH - Cytochrome P-450 Enzyme System/*genetics MH - Fasciola hepatica/drug effects MH - Fenbendazole/*administration & dosage MH - Gene Expression/drug effects MH - Isoenzymes/genetics MH - Liver/*enzymology MH - Male MH - Oxygenases/*genetics MH - RNA, Messenger/analysis MH - Real-Time Polymerase Chain Reaction/veterinary MH - Triclabendazole/*administration & dosage OTO - NOTNLM OT - Benzimidazole anthelmintics OT - Cattle liver slices OT - Cytochrome P450 isoenzymes OT - Flavin-monooxygenases OT - beta-naphtoflavone EDAT- 2019/03/02 06:00 MHDA- 2019/04/24 06:00 CRDT- 2019/03/02 06:00 PHST- 2018/06/23 00:00 [received] PHST- 2019/01/11 00:00 [revised] PHST- 2019/01/14 00:00 [accepted] PHST- 2019/03/02 06:00 [entrez] PHST- 2019/03/02 06:00 [pubmed] PHST- 2019/04/24 06:00 [medline] AID - S1090-0233(18)30304-6 [pii] AID - 10.1016/j.tvjl.2019.01.001 [doi] PST - ppublish SO - Vet J. 2019 Mar;245:61-69. doi: 10.1016/j.tvjl.2019.01.001. Epub 2019 Jan 15.