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J Biol Chem, Vol. 275, Issue 10, 6741-6748, March 10, 2000
N-t-Butyl Hydroxylamine, a Hydrolysis
Product of -Phenyl-N-t-butyl Nitrone, Is
More Potent in Delaying Senescence in Human Lung Fibroblasts*
Hani
Atamna,
Andrés
Paler-Martínez, and
Bruce N.
Ames
From the Division of Biochemistry and Molecular Biology, Department
of Molecular and Cell Biology, University of California,
Berkeley, California 94720-3202
-Phenyl-N-t-butyl
nitrone (PBN), a spin trap, scavenges hydroxyl radicals, protects
tissues from oxidative injury, and delays senescence of both normal
human lung fibroblasts (IMR90) and senescence-accelerated mice.
N-t-butyl hydroxylamine and benzaldehyde are
the breakdown products of PBN. N-t-Butyl
hydroxylamine delays senescence of IMR90 cells at concentrations as low
as 10 µM compared with 200 µM PBN to
produce a similar effect, suggesting that
N-t-butyl hydroxylamine is the active form of
PBN. N-Benzyl hydroxylamine and N-methyl
hydroxylamine compounds unrelated to PBN were also effective in
delaying senescence, suggesting the active functional group is the
N-hydroxylamine. All the N-hydroxylamines
tested significantly decreased the endogenous production of oxidants, as measured by the oxidation of 2',7'-dichlorodihydrofluorescin and the
increase in the GSH/GSSG ratio. The acceleration of senescence induced
by hydrogen peroxide is reversed by the N-hydroxylamines. DNA damage, as determined by the level of apurinic/apyrimidinic sites,
also decreased significantly following treatment with
N-hydroxylamines. The N-hydroxylamines appear
to be effective through mitochondria; they delay
age-dependent changes in mitochondria as measured by accumulation of rhodamine-123, they prevent reduction of cytochrome CFeIII by superoxide radical, and they reverse an
age-dependent decay of mitochondrial aconitase, suggesting
they react with the superoxide radical.
*
This work was supported by National Institutes of Health
Grants AG17140 (NIA), Outstanding Investigator Grant CA39910 (NCI), and
Center Grant ES01896 (NIEHS) (to B. N. A.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence and reprint requests should be addressed:
Division of Biochemistry and Molecular Biology, CHORI, 5700 Martin
Luther King Jr. Way, Oakland, CA 94609. Tel.: 510-450-7625; Fax:
510-597-7128; E-mail: bnames@uclink4.berkeley.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 2000 by the American Society for Biochemistry and Molecular Biology.
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