title: The immature rat as a potential model for chemical risks to children: Ontogeny of selected hepatic P450s.
abstract: Concern about potential susceptibilities of infants and children to chemicals has led to the consideration of immature rodents as potential test surrogates. Maturation of some hepatic microsomal cytochrome P450s (CYPs), that participate in metabolic activation of organic solvents and polycyclic aromatic hydrocarbons (PAHs), may differ significantly between humans and rodents. The present investigation was undertaken to delineate the ontogeny of selected hepatic CYPs in male and female Sprague-Dawley (S-D) rats, and to contrast them with developmental profiles in humans. Microsomes were prepared from the liver of sexed and unsexed postnatal day (PND) 1-90 rats, and total CYP450 levels, as well as CYP1A1/2, CYP2E1 and CYP2B1/2 activities and protein, were quantified. CYP1A1/2 and CYP2E1 activity and expression rose rapidly after birth, peaked from PND 21-40/50, and declined substantially to adult values by PND 90. The same ontogenic profiles were manifested when the enzyme activities were expressed per entire liver or liver normalized to body weight. CYP1A1/2 and CYP2E1 activity and protein expression were well correlated. CYP2B1/2 activity peaked abruptly on PND 21 and declined irregularly to adult values. These patterns are in contrast to human CYP1A2 and CYP2E1, which are reported to progressively increase in liver during the first few months to years of life. The three CYP protein developmental profiles were largely gender independent in rats. The immature rat does not appear to be a suitable model for assessing risks posed to infants and children by chemicals metabolically activated by CYP2E1, based on the findings of greater carbon tetrachloride hepatotoxicity in preweanlings and weanlings than in adult animals. Additional studies are required to determine whether immature S-D rats may be used as an animal model for substrates of other CYPs, as total CYP450 levels in the liver progressively rose during maturation, similarly to humans.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy and Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602, USA.
authors.forename: Brooks T
authors.initials: BT
authors.lastname: McPhail
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy and Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: White
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy and Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602, USA.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Cummings
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy and Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602, USA.
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Muralidhara
authors.affiliation: ATSDR, Division of Toxicology and Human Health Sciences, Department of Health and Human Services, Atlanta, GA 30333, USA.
authors.forename: Jewell T
authors.initials: JT
authors.lastname: Wilson
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy and Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602, USA. Electronic address: bruckner@uga.edu.
authors.forename: James V
authors.initials: JV
authors.lastname: Bruckner
mesh_terms: D065767:Activation, Metabolic / Q000187:drug effects; D000367:Age Factors; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002648:Child; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D013250:Steroid Hydroxylases / Q000378:metabolism
chemical_list: D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; D013250:Steroid Hydroxylases; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D019362:Cytochrome P-450 CYP2B1; C025619:steroid 16-beta-hydroxylase
keywords: Animal model; Carbon tetrachloride; Children’s risk assessment; Cytochrome P450 ontogeny; Hepatotoxicity; Metabolic activation