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Protein restoration in low-birth-weight rat offspring derived from maternal low-protein diet leads to elevated hepatic CYP3A and CYP2C11 activity in adulthood.
- Source :
-
Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2014 Feb; Vol. 42 (2), pp. 221-8. Date of Electronic Publication: 2013 Nov 08. - Publication Year :
- 2014
-
Abstract
- The World Health Organization has identified hypercholesterolemia to be one of the major symptoms encompassing the metabolic syndrome. Moreover, epidemiologic evidence indicates that low-birth-weight offspring are at greater risk of developing the metabolic syndrome. Previous work in our laboratory demonstrated that maternal protein restriction (MPR) results in impaired fetal growth and hypercholesterolemia in adulthood. This was attributed to repression of hepatic CYP7A1, a rate-limiting enzyme that catabolizes cholesterol to bile acids. Another important function of hepatic cytochrome P450 enzymes is the phase I oxidative metabolism of drugs (i.e., statins for hypercholesterolemia), which can significantly impact pharmacokinetics. We hypothesized that MPR offspring may have altered ability to metabolize drugs in adulthood. To address this hypothesis, we maintained Wistar rats on a 20% protein diet (control) or a low 8% protein diet throughout prenatal and postnatal life (LP1) or exclusively during prenatal life and weaning (LP2). Intriguingly CYP3A and CYP2C11 intrinsic clearance (Vmax/Km) was significantly increased exclusively in LP2 offspring at postnatal day 130 compared with control or LP1 offspring, as evaluated by testosterone enzyme kinetics in liver microsomes. The increase in activity was secondary to an increase in CYP3A23 and CYP2C11 mRNA. Collectively, these findings suggest that a low-birth-weight offspring with postnatal catch-up growth may have a diminished response to xenobiotics metabolized by CYP3A and CYP2C11 enzymes.
- Subjects :
- Age Factors
Animals
Aryl Hydrocarbon Hydroxylases genetics
Cytochrome P-450 CYP3A
Cytochrome P450 Family 2
Female
Gene Expression Regulation, Enzymologic
Kinetics
Lactation
Microsomes, Liver enzymology
Pregnancy
RNA, Messenger metabolism
Rats
Rats, Wistar
Steroid 16-alpha-Hydroxylase genetics
Substrate Specificity
Up-Regulation
Weaning
Animal Nutritional Physiological Phenomena
Aryl Hydrocarbon Hydroxylases metabolism
Birth Weight
Diet, Protein-Restricted
Dietary Proteins metabolism
Liver enzymology
Maternal Nutritional Physiological Phenomena
Steroid 16-alpha-Hydroxylase metabolism
Testosterone metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1521-009X
- Volume :
- 42
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Drug metabolism and disposition: the biological fate of chemicals
- Publication Type :
- Academic Journal
- Accession number :
- 24212381
- Full Text :
- https://doi.org/10.1124/dmd.113.053538