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Ontogenesis of phase I hepatic drug metabolic enzymes in sheep
- Source :
- Reproduction, Fertility and Development. 24:425
- Publication Year :
- 2012
- Publisher :
- CSIRO Publishing, 2012.
-
Abstract
- Cytochrome P450 (CYP) enzymes are important for the metabolism of many drugs. While there is information on their identity and ontogeny in humans and rodents, similar data in sheep are lacking. In the present study, cDNA sequences of several CYP enzymes (CYP2A6, CYP2C19, CYP2D6) were cloned by rapid amplification of cDNA ends. In adult, newborn and fetal sheep the mRNA and protein levels of these CYPs and the regulatory factor, hepatic nuclear factor 4α (HNF4α) were determined in liver samples using real-time PCR and western blotting. The effect of antenatal glucocorticoid on these enzymes was also studied by i.v. infusion of cortisol (0.45 mg h–1; 80 h) to another group of fetuses. The mRNA and protein levels of the CYPs and HNF4α were low or absent in the fetus, followed by increasing levels in the newborn and adult. Fetal cortisol administration significantly increased the mRNA and protein levels of CYP2D6. Moreover, the correlation observed between the CYP and HNF4α mRNA levels suggests a possible regulatory role for this transcription factor. The findings suggest that fetal and newborn lambs have a low ability to metabolise drugs that are substrates of these enzymes, and that this ability increases with advancing postnatal age, similar to the situation in humans.
- Subjects :
- Male
medicine.medical_specialty
Reproductive technology
Biology
Gene Expression Regulation, Enzymologic
Fetus
Endocrinology
Cytochrome P-450 Enzyme System
Rapid amplification of cDNA ends
Internal medicine
Genetics
medicine
Animals
RNA, Messenger
Cloning, Molecular
CYP2A6
Molecular Biology
chemistry.chemical_classification
Sheep
Age Factors
Gene Expression Regulation, Developmental
Cytochrome P450
Sequence Analysis, DNA
Enzyme
Animals, Newborn
Liver
Reproductive Medicine
chemistry
Hepatocyte nuclear factor 4
biology.protein
Female
Metabolic Detoxication, Phase I
Animal Science and Zoology
Glucocorticoid
Developmental Biology
Biotechnology
medicine.drug
Subjects
Details
- ISSN :
- 10313613
- Volume :
- 24
- Database :
- OpenAIRE
- Journal :
- Reproduction, Fertility and Development
- Accession number :
- edsair.doi.dedup.....ded97c73b16f2cd8fd361ed446b43efe
- Full Text :
- https://doi.org/10.1071/rd11159