title: Protein restoration in low-birth-weight rat offspring derived from maternal low-protein diet leads to elevated hepatic CYP3A and CYP2C11 activity in adulthood.
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.
authors.affiliation: The Children's Health Research Institute (G.S., D.B.H.) and the Lawson Health Research Institute (G.S., D.B.H., B.L.U.), Department of Obstetrics and Gynecology (G.S., D.B.H.) and Physiology and Pharmacology (G.S., E.J.B., T.J.V., B.L.U., D.B.H.), University of Western Ontario, London, Ontario, Canada.
authors.forename: Gurjeev
authors.initials: G
authors.lastname: Sohi
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Barry
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Velenosi
authors.forename: Bradley L
authors.initials: BL
authors.lastname: Urquhart
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Hardy
mesh_terms: D000367:Age Factors; D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D001724:Birth Weight; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D018753:Diet, Protein-Restricted; D004044:Dietary Proteins / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D007700:Kinetics; D007774:Lactation; D008099:Liver / Q000201:enzymology*; D039382:Maternal Nutritional Physiological Phenomena; D008862:Microsomes, Liver / Q000201:enzymology; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D039181:Steroid 16-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D013739:Testosterone / Q000378:metabolism*; D015854:Up-Regulation; D014886:Weaning
chemical_list: D004044:Dietary Proteins; D012333:RNA, Messenger; D013739:Testosterone; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase