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J Biol Chem, Vol. 275, Issue 3, 2003-2008, January 21, 2000
From the Department of Hygiene, Mie University School of Medicine,
Tsu, Mie, 514-8507, Japan
Recent intervention studies revealed that
Oxidative DNA Damage by Vitamin A and Its Derivative via
Superoxide Generation*
-carotene supplement to smokers resulted in a higher incidence of
lung cancer. However, the causal mechanisms remain to be clarified. We
reported here that vitamin A (retinol) and its derivative (retinal)
caused cellular DNA cleavage detected by pulsed field gel
electrophoresis. Retinol and retinal significantly induced
8-oxo-7,8-dihydro-2'-deoxyguanosine formation in HL-60 cells but not in
H2O2-resistant HP100 cells, suggesting
the involvement of H2O2 in cellular DNA damage.
Experiments using 32P-labeled isolated DNA demonstrated
that retinol and retinal caused Cu(II)-mediated DNA damage, which was
inhibited by catalase. UV-visible spectroscopic and electron spin
resonance-trapping studies revealed the generation of superoxide and
carbon-centered radicals, respectively. The superoxide generation
during autoxidation of retinoids was significantly correlated with the
formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine, although the yield of
carbon-centered radicals was not necessarily related to the intensity
of DNA damage. These findings suggest that superoxide generated by
autoxidation of retinoids was dismutated to
H2O2, which was responsible for DNA damage in
the presence of endogenous metals. Retinol and retinal have prooxidant
abilities, which might lead to carcinogenesis of the supplements of
-carotene.
*
This work was supported in part by a grant-in-aid for
Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan.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 requests for reprints should be
addressed: Dept. of Hygiene, Mie University School of Medicine, 2-174, Edobashi, Tsu, Mie, 514-8507, Japan. Tel. and Fax: 81 59 231 5011;
E-mail: kawanisi@doc.medic.mie-u.ac.jp.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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