title: Embryonic catalase protects against endogenous and phenytoin-enhanced DNA oxidation and embryopathies in acatalasemic and human catalase-expressing mice.
abstract: Oxidative stress and reactive oxygen species (ROS) such as hydrogen peroxide (H(2)O(2)), which is detoxified by catalase, are implicated in fetal death and birth defects. However, embryonic levels of catalase are only ∼ 5% of adult activity, and its protective role is not understood completely. Herein, we used mutant catalase-deficient mice [acatalasemic (aCat)] and transgenic mice expressing human catalase (hCat), which, respectively, exhibited 40-50% reductions and 2-fold elevations in the activities of embryonic and fetal brain catalase, to show that embryonic catalase protects the embryo from both physiological oxidative stress and the ROS-initiating antiepileptic drug phenytoin. Compared to wild-type (WT) catalase-normal controls, both untreated and phenytoin-exposed aCat mice exhibited a 30% increase in embryonic DNA oxidation and a >2-fold increase in embryopathies, both of which were completely blocked by protein therapy with exogenous catalase. Conversely, compared to WT controls, untreated and, to a lesser extent, phenytoin-exposed hCat mice were protected, with untreated hCat embryos exhibiting a 40% decrease in embryonic DNA oxidation and up to a 67% decrease in embryopathies. Embryonic catalase accordingly plays an important protective role, and both physiological and phenytoin-enhanced oxidative stress can be embryopathic.
authors.affiliation: Faculty of Pharmacy, University of Toronto, 144 College St., Toronto, ON, Canada.
authors.forename: Julia P
authors.initials: JP
authors.lastname: Abramov
authors.forename: Peter G
authors.initials: PG
authors.lastname: Wells
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D020642:Acatalasia / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000633:toxicity; D001921:Brain / Q000002:abnormalities / Q000187:drug effects / Q000201:enzymology; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000201:enzymology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010084:Oxidation-Reduction / Q000187:drug effects; D010672:Phenytoin / Q000378:metabolism / Q000633:toxicity*; D011247:Pregnancy; D015996:Survival Rate
chemical_list: D000927:Anticonvulsants; D010672:Phenytoin; D004247:DNA; D002374:Catalase