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Age-related differences in CYP3A abundance and activity in the liver of the Gottingen Minipig

Els Van Peer, Lies De Bock, Koen Boussery UGent, Jan Van Bocxlaer UGent, Christophe Casteleyn, Chris Van Ginneken and Steven Van Cruchten (2015) BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY. 117(5). p.350-357
abstract
In view of paediatric drug development, regulatory authorities often request safety studies in juvenile animals, including minipigs. Unfortunately, knowledge on the ontogeny of the biotransformation processes in animal models remains scarce and impedes a correct interpretation of the toxicity findings. CYP3A4 is one of the most important drug-metabolizing enzymes in human beings and shows important similarities with CYP3A in the minipig. Therefore, the aim of this study was to assess the abundance and activity of CYP3A in liver microsomes from foetal, juvenile (days 1, 3, 7 and 28) and adult male and female Gottingen minipigs. CYP3A abundance was studied by an indirect enzyme-linked immunosorbent assay (ELISA), whereas CYP3A activity was assessed by a biotransformation assay with Luciferin-IPA. CYP3A abundance could not be detected until day 3. From day 7 onwards, a gradual increase in expression was noted, leading to the highest abundance in adult animals. CYP3A activity was not detectable in foetuses and 1-day-old animals. The CYP3A activity was detectable, but below the LLOQ in day 3 animals and increased gradually with age to reach the highest level in adults. The CYP3cide and ketoconazole inhibition, and testosterone and midazolam reduction of Luciferin-IPA metabolism in minipig liver microsomes substantiate that Luciferin-IPA is metabolized by CYP3A in minipigs. A positive correlation was found between CYP3A abundance and biotransformation of Luciferin-IPA (Pearson r = 0.863; p < 0.0001). In conclusion, both abundance and activity of CYP3A increased gradually in juvenile minipigs, but remained below the levels observed in adult animals.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
minipig, ELISA, CYP3A, juvenile animals, safety studies, CYTOCHROME-P450 ISOFORMS, DRUG-METABOLISM, SEX-DIFFERENCES, MINIATURE PIGS, MESSENGER-RNA, MICROSOMES, EXPRESSION, VARIABILITY, ONTOGENY, ENZYMES
journal title
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
Basic Clin. Pharmacol. Toxicol.
volume
117
issue
5
pages
350 - 357
Web of Science type
Article
Web of Science id
000362647600009
JCR category
TOXICOLOGY
JCR impact factor
3.097 (2015)
JCR rank
24/89 (2015)
JCR quartile
2 (2015)
ISSN
1742-7835
DOI
10.1111/bcpt.12410
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
7042848
handle
http://hdl.handle.net/1854/LU-7042848
date created
2016-01-18 16:29:21
date last changed
2016-12-19 15:39:13
@article{7042848,
  abstract     = {In view of paediatric drug development, regulatory authorities often request safety studies in juvenile animals, including minipigs. Unfortunately, knowledge on the ontogeny of the biotransformation processes in animal models remains scarce and impedes a correct interpretation of the toxicity findings. CYP3A4 is one of the most important drug-metabolizing enzymes in human beings and shows important similarities with CYP3A in the minipig. Therefore, the aim of this study was to assess the abundance and activity of CYP3A in liver microsomes from foetal, juvenile (days 1, 3, 7 and 28) and adult male and female Gottingen minipigs. CYP3A abundance was studied by an indirect enzyme-linked immunosorbent assay (ELISA), whereas CYP3A activity was assessed by a biotransformation assay with Luciferin-IPA. CYP3A abundance could not be detected until day 3. From day 7 onwards, a gradual increase in expression was noted, leading to the highest abundance in adult animals. CYP3A activity was not detectable in foetuses and 1-day-old animals. The CYP3A activity was detectable, but below the LLOQ in day 3 animals and increased gradually with age to reach the highest level in adults. The CYP3cide and ketoconazole inhibition, and testosterone and midazolam reduction of Luciferin-IPA metabolism in minipig liver microsomes substantiate that Luciferin-IPA is metabolized by CYP3A in minipigs. A positive correlation was found between CYP3A abundance and biotransformation of Luciferin-IPA (Pearson r = 0.863; p {\textlangle} 0.0001). In conclusion, both abundance and activity of CYP3A increased gradually in juvenile minipigs, but remained below the levels observed in adult animals.},
  author       = {Van Peer, Els and De Bock, Lies and Boussery, Koen and Van Bocxlaer, Jan and Casteleyn, Christophe and Van Ginneken, Chris and Van Cruchten, Steven},
  issn         = {1742-7835},
  journal      = {BASIC \& CLINICAL PHARMACOLOGY \& TOXICOLOGY},
  keyword      = {minipig,ELISA,CYP3A,juvenile animals,safety studies,CYTOCHROME-P450 ISOFORMS,DRUG-METABOLISM,SEX-DIFFERENCES,MINIATURE PIGS,MESSENGER-RNA,MICROSOMES,EXPRESSION,VARIABILITY,ONTOGENY,ENZYMES},
  language     = {eng},
  number       = {5},
  pages        = {350--357},
  title        = {Age-related differences in CYP3A abundance and activity in the liver of the Gottingen Minipig},
  url          = {http://dx.doi.org/10.1111/bcpt.12410},
  volume       = {117},
  year         = {2015},
}

Chicago
Van Peer, Els, Lies De Bock, Koen Boussery, Jan Van Bocxlaer, Christophe Casteleyn, Chris Van Ginneken, and Steven Van Cruchten. 2015. “Age-related Differences in CYP3A Abundance and Activity in the Liver of the Gottingen Minipig.” Basic & Clinical Pharmacology & Toxicology 117 (5): 350–357.
APA
Van Peer, E., De Bock, L., Boussery, K., Van Bocxlaer, J., Casteleyn, C., Van Ginneken, C., & Van Cruchten, S. (2015). Age-related differences in CYP3A abundance and activity in the liver of the Gottingen Minipig. BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY, 117(5), 350–357.
Vancouver
1.
Van Peer E, De Bock L, Boussery K, Van Bocxlaer J, Casteleyn C, Van Ginneken C, et al. Age-related differences in CYP3A abundance and activity in the liver of the Gottingen Minipig. BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY. 2015;117(5):350–7.
MLA
Van Peer, Els, Lies De Bock, Koen Boussery, et al. “Age-related Differences in CYP3A Abundance and Activity in the Liver of the Gottingen Minipig.” BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY 117.5 (2015): 350–357. Print.