From: Doug Skrecky (oberon@vcn.bc.ca)
Date: Fri Nov 06 1998 - 23:40:21 MST
Citations: 1-2
<1>
Authors
Tirmenstein MA. Leraas TL. Fariss MW.
Institution
Department of Pharmaceutical Sciences, College of Pharmacy and Graduate
Program in Pharmacology/Toxicology, Washington State University, Pullman
99164-6510, USA.
Title
alpha-Tocopheryl hemisuccinate
administration increases rat liver subcellular alpha-tocopherol levels and
protects against carbon tetrachloride-induced hepatotoxicity.
Source
Toxicology Letters. 92(1):67-77, 1997 Jun 16.
Abstract
Rats were administered a series of tocopherol analogs 18 h prior to a
hepatotoxic dose of carbon tetrachloride (CCl4). Of the compounds tested,
only d-alpha-tocopheryl hemisuccinate (TS)
provided significant protection against CCl4-induced hepatotoxicity. No
protection was observed with either d-alpha-tocopherol (alpha-T) or a
tocopherol succinate ether derivative,
d-alpha-tocopheryloxybutyric acid (TSE). None of the
tocopherol analogs significantly inhibited CYP2E1 activity as measured by
oxidation of p-nitrophenol. Liver homogenates and subcellular fractions
(cytosol, nuclei, plasma membranes, mitochondria and microsomes) were
collected 18 h after tocopherol analog administration in the absence of CCl4.
Homogenate and subcellular alpha-T levels were not significantly increased
following TSE administration but were increased 2-3 fold following TS and
alpha-T administration. Total tocopherol levels (alpha-T+ TS + TSE) in liver
homogenates and subcellular fractions were highest in rats supplemented with
TS. In these animals, TS was detected in all subcellular fractions and total
tocopherol levels were increased from 6-23 fold over those seen in controls
and 2-9 fold over alpha-T treated rats. In vitro studies in which liver
homogenates and subcellular fractions were peroxidized with ascorbate and
ADP/Fe suggest that increasing levels of alpha-T but not TS correlates with
increased protection against lipid peroxidation. These results suggest that
the ability of TS to protect against CCl4-induced hepatotoxicity relates to
its enhanced hepatic accumulation and subsequent hydrolysis to alpha-T.
<2>
Authors
Fariss MW. Fortuna MB. Everett CK. Smith JD. Trent DF. Djuric Z.
Institution
Department of Pathology, Medical College of Virginia, Virginia Commonwealth
University, Richmond 23298-0662.
Title
The selective antiproliferative effects of alpha-tocopheryl
hemisuccinate and cholesteryl hemisuccinate
on murine leukemia cells result from the action of the intact compounds.
Source
Cancer Research. 54(13):3346-51, 1994 Jul 1.
Abstract
In the present study we have established that the antitumor activity of
alpha-tocopheryl succinate (TS, vitamin E succinate) and
cholesteryl succinate (CS) result from the action of the intact TS and CS
compounds and not from the release of alpha-tocopherol, cholesterol, or
succinate. We report that treatment of murine leukemia cell lines C1498
(myeloid) and L1210 (lymphocytic), with the tris salts of TS or CS, but not
alpha-tocopherol and tris succinate or cholesterol and tris succinate,
significantly inhibit the growth of these tumor cells and significantly
enhance doxorubicin-induced tumor cell kill in a similar fashion. In
contrast, the treatments mentioned above did not adversely affect the growth
of murine normal bone marrow cells (colony-forming
unit-granulocyte-macrophage). In fact, colony-forming unit
granulocyte-macrophage cell growth was stimulated by exposure to CS and TS
(as well as their ether analogues) at concentrations above 100 microM.
Furthermore, pretreatment of colony-forming unit granulocyte-macrophage cells
with TS or CS appears to protect these normal cells from the lethal effect of
doxorubicin exposure. Selective inhibition of leukemia cell proliferation
(identical to that noted for CS and TS) was also observed following the
treatment of cells with the nonhydrolyzable ether forms of CS
(cholesteryloxybutyric acid) and TS
(alpha-tocopheryloxybutyric acid). These findings suggest
that TS, alpha-tocopheryloxybutyric acid, CS, and
cholesteryloxybutyric acid may prove clinically useful as selective antitumor
agents when administered alone or in combination with doxorubicin by a route
that ensures tissue accumulation of the intact compound.
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