PMID- 38141570
OWN - NLM
STAT- MEDLINE
DCOM- 20240116
LR  - 20240116
IS  - 1532-2661 (Electronic)
IS  - 0034-5288 (Linking)
VI  - 167
DP  - 2024 Feb
TI  - Unravelling drug-drug interactions in pigs: Induction of hepatic cytochrome P450 
      1A (CYP1A) metabolism after the in-feed medication with the anthelmintic 
      fenbendazole.
PG  - 105113
LID - S0034-5288(23)00364-8 [pii]
LID - 10.1016/j.rvsc.2023.105113 [doi]
AB  - The anthelmintic fenbendazole (FBZ) undergoes hepatic S‑oxygenation by 
      monooxygenases belonging to the cytochrome P450 (CYP) and flavin-monooxygenase 
      (FMO) families. The in-feed medication with FBZ induced CYP1A-dependent 
      metabolism in pig liver. This fact may alter the metabolism of the anthelmintic 
      itself, and of CYP1A substrates like aflatoxin B1 (AFB1). This work evaluated the 
      effect of the in-feed administration of FBZ on CYP1A-dependent metabolism, on its 
      own pattern of hepatic S‑oxygenation, and on the metabolism of AFB1. Landrace 
      piglets remained untreated (n = 5) or received a pre-mix of FBZ (n = 6) in feed 
      for 9 days. Pigs were slaughtered for preparation of liver microsomes used for: 
      CYP content determination; monitoring the CYP1A-dependent enzyme activities, 
      7-ethoxyresorufin O-deethylase (EROD) and 7-methoxyresorufin O-demethylase 
      (MROD); measurement of FBZ (50 muM) S‑oxygenation, and AFB1 (16 nM) disappearance 
      from the incubation medium. In microsomes of FBZ-treated animals, EROD and MROD 
      increased 19-fold (p = 0.002) and 14-fold (p = 0.003), respectively. An enhanced 
      (3-fold, p = 0.004) participation of the CYP pathway in FBZ S‑oxygenation was 
      observed in the liver of piglets treated with the anthelmintic 
      (210 +/- 69 pmol/min.nmol CYP) compared to untreated animals (68 +/- 34 pmol/min.nmol 
      CYP). AFB1 metabolism was 93% higher (p = 0.009) in the liver of FBZ-treated 
      compared to untreated pigs. Positive and significant (p < 0.05) correlations were 
      observed between CYP1A-dependent enzyme activities and FBZ or AFB1 metabolism. 
      The sustained administration of FBZ caused an auto-induction of the 
      CYP1A-dependent S‑oxygenation of this anthelmintic. The CYP1A induction triggered 
      by the anthelmintic could amplify the production of AFB1 metabolites in pig 
      liver, including the hepatotoxic AFB1-derived epoxide.+.
CI  - Copyright (c) 2023 Elsevier Ltd. All rights reserved.
FAU - Ichinose, Paula
AU  - Ichinose P
AD  - Universidad Nacional del Centro de la Provincia de Buenos Aires (UNCPBA), 
      Facultad de Ciencias Veterinarias, Tandil, Buenos Aires, Argentina; Centro de 
      Investigacion Veterinaria de Tandil (CIVETAN), UNCPBA-CICPBA-CONICET, Tandil, 
      Buenos Aires, Argentina.
FAU - Miro, Maria Victoria
AU  - Miro MV
AD  - Universidad Nacional del Centro de la Provincia de Buenos Aires (UNCPBA), 
      Facultad de Ciencias Veterinarias, Tandil, Buenos Aires, Argentina; Centro de 
      Investigacion Veterinaria de Tandil (CIVETAN), UNCPBA-CICPBA-CONICET, Tandil, 
      Buenos Aires, Argentina.
FAU - Larsen, Karen
AU  - Larsen K
AD  - Universidad Nacional del Centro de la Provincia de Buenos Aires (UNCPBA), 
      Facultad de Ciencias Veterinarias, Tandil, Buenos Aires, Argentina; Centro de 
      Investigacion Veterinaria de Tandil (CIVETAN), UNCPBA-CICPBA-CONICET, Tandil, 
      Buenos Aires, Argentina.
FAU - Lifschitz, Adrian
AU  - Lifschitz A
AD  - Universidad Nacional del Centro de la Provincia de Buenos Aires (UNCPBA), 
      Facultad de Ciencias Veterinarias, Tandil, Buenos Aires, Argentina; Centro de 
      Investigacion Veterinaria de Tandil (CIVETAN), UNCPBA-CICPBA-CONICET, Tandil, 
      Buenos Aires, Argentina.
FAU - Virkel, Guillermo
AU  - Virkel G
AD  - Universidad Nacional del Centro de la Provincia de Buenos Aires (UNCPBA), 
      Facultad de Ciencias Veterinarias, Tandil, Buenos Aires, Argentina; Centro de 
      Investigacion Veterinaria de Tandil (CIVETAN), UNCPBA-CICPBA-CONICET, Tandil, 
      Buenos Aires, Argentina. Electronic address: gvirkel@vet.unicen.edu.ar.
LA  - eng
PT  - Journal Article
DEP - 20231219
PL  - England
TA  - Res Vet Sci
JT  - Research in veterinary science
JID - 0401300
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP1A1)
RN  - 621BVT9M36 (Fenbendazole)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - 0 (Anthelmintics)
SB  - IM
MH  - Humans
MH  - Animals
MH  - Swine
MH  - *Cytochrome P-450 CYP1A1/metabolism/pharmacology
MH  - Fenbendazole/pharmacology/metabolism
MH  - Cytochrome P-450 Enzyme System/metabolism
MH  - *Anthelmintics/pharmacology
MH  - Microsomes, Liver/metabolism
MH  - Drug Interactions
OTO - NOTNLM
OT  - Aflatoxin B1
OT  - Cytochrome P450
OT  - Enzyme induction
OT  - Fenbendazole
OT  - Liver
OT  - Pigs
COIS- Declaration of Competing Interest All authors have none conflict(s) of interest 
      to declare.
EDAT- 2023/12/24 09:41
MHDA- 2024/01/16 06:41
CRDT- 2023/12/23 18:14
PHST- 2023/10/12 00:00 [received]
PHST- 2023/12/12 00:00 [revised]
PHST- 2023/12/14 00:00 [accepted]
PHST- 2024/01/16 06:41 [medline]
PHST- 2023/12/24 09:41 [pubmed]
PHST- 2023/12/23 18:14 [entrez]
AID - S0034-5288(23)00364-8 [pii]
AID - 10.1016/j.rvsc.2023.105113 [doi]
PST - ppublish
SO  - Res Vet Sci. 2024 Feb;167:105113. doi: 10.1016/j.rvsc.2023.105113. Epub 2023 Dec 
      19.