title: The ontogeny and population variability of human hepatic dihydronicotinamide riboside:quinone oxidoreductase (NQO2).
abstract: Dihydronicotinamide riboside:quinone oxidoreductase (NQO2) is an enzyme that performs reduction reactions involved in antioxidant defense. We hypothesized that NQO2 hepatic drug clearance would develop in children over time, similar to NQO1. Using human liver cytosol (n = 117), the effects of age, sex, ethnicity, and weight on NQO2 expression and activity were probed. No significant correlations were observed. Biochemical activity of NQO2 was as high at birth as in adults (0.23 ± 0.04 nmol/min/mg protein, mean ± SEM, range 0-1.83). In contrast, modeled hepatic clearance through the NQO2 pathway was up to 10% of adult levels at birth, reaching predicted adult levels (0.3 ± 0.03 L/h) at 14 years of age. Comparisons between NQO1 and NQO2 in the same livers showed that neither protein (P = 0.32) nor activity (P = 0.23) correlated, confirming both orthologs are independently regulated. Because hepatic clearance through NQO2 does not mature until teenage years, compounds detoxified by this enzyme may be more deleterious in children.
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Riches
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
authors.forename: Yuejian
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Berman
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
authors.forename: Gurinder
authors.initials: G
authors.lastname: Walia
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
authors.forename: Abby C
authors.initials: AC
authors.lastname: Collier
mesh_terms: D000375:Aging / Q000378:metabolism*; D005260:Female; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D011808:Quinone Reductases / Q000378:metabolism*
chemical_list: D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases
keywords: antioxidants; drug metabolism; in vitro-in vivo extrapolation; pediatric; physiologically based pharmacokinetic modeling