title: Ontogenic differences in human liver 4-hydroxynonenal detoxification are associated with in vitro injury to fetal hematopoietic stem cells.
abstract: 4-hydroxynonenal (4HNE) is a highly mutagenic and cytotoxic alpha,beta-unsaturated aldehyde that can be produced in utero during transplacental exposure to prooxidant compounds. Cellular protection against 4HNE injury is provided by alcohol dehydrogenases (ADH), aldehyde reductases (ALRD), aldehyde dehydrogenases (ALDH), and glutathione S-transferases (GST). In the present study, we examined the comparative detoxification of 4HNE by aldehyde-metabolizing enzymes in a panel of adult and second-trimester prenatal liver tissues and report the toxicological ramifications of ontogenic 4HNE detoxification in vitro. The initial rates of 4HNE oxidation and reduction were two- to fivefold lower in prenatal liver subcellular fractions as compared to adult liver, and the rates of GST conjugation of 4HNE were not detectable in either prenatal or adult cytosolic fractions. GSH-affinity purification of hepatic cytosol yielded detectable and roughly equivalent rates of GST-4HNE conjugation for the two age groups. Consistent with the inefficient oxidative and reductive metabolism of 4HNE in prenatal liver, cytosolic fractions prepared from prenatal liver exhibited a decreased ability to protect against 4HNE-protein adduct formation relative to adults. Prenatal liver hematopoietic stem cells (HSC), which constitute a significant percentage of prenatal liver cell populations, exhibited ALDH activities toward 4HNE, but little reductive or conjugative capacity toward 4HNE through ALRD, ADH, and GST. Cultured HSC exposed to 5 microM 4HNE exhibited a loss in viability and readily formed one or more high molecular weight 4HNE-protein adduct(s). Collectively, our results indicate that second trimester prenatal liver has a lower ability to detoxify 4HNE relative to adults, and that the inefficient detoxification of 4HNE underlies an increased susceptibility to 4HNE injury in sensitive prenatal hepatic cell targets.
authors.affiliation: Department of Physiological Sciences, Center for Environmental and Human Toxicology, P.O. Box 110885, University of Florida, Gainesville, FL 32611, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Gardner
authors.forename: Adriana M
authors.initials: AM
authors.lastname: Doi
authors.forename: Robert T
authors.initials: RT
authors.lastname: Pham
authors.forename: Christiaan M
authors.initials: CM
authors.lastname: Huisden
authors.forename: Evan P
authors.initials: EP
authors.lastname: Gallagher
mesh_terms: D000328:Adult; D000447:Aldehydes / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism; D005333:Fetus / Q000187:drug effects / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008658:Inactivation, Metabolic; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000447:Aldehydes; C027576:4-hydroxy-2-nonenal