Details

Autor(en) / Beteiligte

• McPhail, Brooks T.
• White, Catherine A.
• Cummings, Brian S.
• Muralidhara, Srinivasa
• Wilson, Jewell T.
• Bruckner, James V.

Titel

The immature rat as a potential model for chemical risks to children: Ontogeny of selected hepatic P450s

Ist Teil von

• Chemico-biological interactions, 2016-08, Vol.256, p.167-177

Ort / Verlag

Ireland: Elsevier Ireland Ltd

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. •Hepatic total CYP450 levels progressively rise during maturation of rats.•Hepatic CYP2E1, 1A1/2 and 2B1/2 activities and protein peak around weaning.•Sex differences in hepatic CYP2E1, 1 A1/2 and 2B1/2 expression are negligible during maturation.•CCl4 is more hepatotoxic to pups than adult rats, paralleling changes in CYP2E1.•Immature rats are not ideal for pediatric assessments of CYP2E1 activated chemicals.